Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

ABSTRACT

Provided herein are methods and compositions for treating cancers, inflammatory diseases, rasopathies, and fibrotic disease involving aberrant Ras superfamily signaling through the binding of compounds to the GTP binding domain of Ras superfamily proteins including, in certain cases, K-Ras and mutants thereof, and a novel method for assaying such compositions.

This application is a continuation of U.S. patent application Ser. No.16/013,872, filed Jun. 20, 2018, which claims the benefit of U.S.Provisional Patent Application No. 62/523,114, filed Jun. 21, 2017, eachof which are incorporated herein by reference in its entirety.

1. FIELD

Provided herein are compositions and methods for treating cancers,inflammatory diseases, rasopathies, and fibrotic disease resulting fromaberrant Ras signaling involving Ras, Rac, Rho, and Cdc42 members of theRas superfamily of proteins through the binding of compounds to the GTPbinding domain of these molecules.

2. BACKGROUND

Pathobiology of Cancer

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites. Clinicaldata and molecular biologic studies indicate that cancer is a multistepprocess that begins with minor preneoplastic changes, which may undercertain conditions progress to neoplasia. The neoplastic lesion mayevolve clonally and develop an increasing capacity for invasion, growth,metastasis, and heterogeneity, especially under conditions in which theneoplastic cells escape the host's immune surveillance. (Roitt, I.,Brostoff, J. and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St.Louis, Mo., 1993))

Various stages of tumor development can be described generally asfollows:

a) Tumor evolution commences when a cell within a normal populationsustains a genetic mutation that expands its tendency to proliferate.

b) Such genetically altered cells and their offspring continue to appearnormal, but they reproduce excessively and lead to a condition termedhyperplasia. The altered cells may also secrete signaling factors orother molecules that cause changes in their local cellular andextracellular environment, including without limitation, the response ofthe immune system to them. Such environmental effects may in turn affectthe viability, proliferation, and further mutations of the alteredcells. After some time (months or years) a very small fraction of thesealtered cells may sustain additional mutation with subsequent loss ofcontrol of cell growth and further potential effects on theirenvironment.

c) The offspring of these cells not only proliferate excessively butalso appear abnormal in shape and in orientation. The tissue is now saidto exhibit a condition termed dysplasia. After some time, one or moreadditional mutations may further alter cell behavior and the effect ofthe cells on their environment.

d) The influenced and genetically altered cells turn still more abnormalin growth and appearance. If the tumor mass does not invade through anyboundaries between tissues, it is termed an in situ tumor. This tumormay stay contained indefinitely, however, some cells may acquire stillmore mutations.

e) A malignant or invasive tumor results if the genetic changes allowthe tumor mass to initiate invading underlying tissue and to cast offcells into the blood or lymph. The defector cells may install new tumorsloci (metastases) throughout the body.

Metastases represent the end products of a multistep cell-biologicalprocess termed the invasion-metastasis cascade, which involvesdissemination of cancer cells to anatomically distant organ sites andtheir subsequent adaptation to foreign tissue microenvironments. Each ofthese events is driven by the acquisition of genetic and/or epigeneticalterations within tumor cells and the co-option of non-neoplasticstromal cells, which together endow incipient metastatic cells withtraits needed to generate macroscopic metastases. (Volastyan, S., etal., Cell, 2011, vol. 147, 275-292)

An enormous variety of cancers affect different tissues throughout thebody, which are described in detail in the medical literature. Over 85%of human cancers are solid tumors, including carcinomas, sarcomas andlymphomas. Different types of solid tumors are named for the type ofcells that form them. Examples include cancer of the lung, colon,rectum, pancreatic, prostate, breast, brain, and intestine. Other humantumors derive from cells involved in the formation of immune cells andother blood cells, including leukemias and myelomas.

The incidence of cancer continues to climb as the general populationages, as new cancers develop, and as susceptible populations grow. Atremendous demand therefore exists for new methods and compositions thatcan be used to treat subjects with cancer.

Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy, biological therapy, targeted therapy, immunotherapy and/orradiation treatment to eradicate neoplastic cells in a patient (see,e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds.,Chapter 12, Section IV; and Baudino TA “Targeted Cancer Therapy: TheNext Generation of Cancer Treatment”, Curr Drug Discov Technol. 2015;12(1):3-20).

Such therapies may be used independently or in combinations. Choices oftherapy will depend on the history and nature of the cancer, thecondition of the patient, and, under the circumstances, the anticipatedefficacy and adverse effects of the therapeutic agents and methodsconsidered.

With respect to chemotherapy, there are a variety of chemotherapeuticagents and methods of delivery of such agents available for thetreatment of different cancers. Most first generation chemotherapeuticagents were not tumor specific, have broad systemic effects, are toxic,and may cause significant and often dangerous side effects, includingsevere nausea, bone marrow depression, and immunosuppression.

Additionally, even with administration of combinations ofchemotherapeutic agents, many tumor cells are or become resistant tochemotherapeutic agents. In fact, cells resistant to the particularchemotherapeutic agents used in a treatment protocol often prove to beresistant to other drugs, even if those agents act by differentmechanism from those of the drugs used in the specific treatment. Thisphenomenon is referred to as multidrug resistance. Because of drugresistance, many cancers prove refractory to standard chemotherapeutictreatment protocols.

Thus, there exists a significant need for alternative compounds,compositions and methods for treating, preventing and managing cancer.

Further, whereas surgical resection and adjuvant therapy can curewell-confined primary tumors, metastatic disease is largely incurablebecause of its systemic nature and the resistance of disseminated tumorcells to existing therapeutic agents. This explains why greater than 90%of mortality from cancer is attributable to metastases, not the primarytumors from which these malignant lesions arise.

Pathobiology of Inflammatory Disease

Inflammation is a complex protective biological response of body tissuesto harmful stimuli, such as pathogens, damaged cells, or irritants,involving immune cells, blood vessels, and molecular mediators. Thefunction of inflammation is to eliminate the initial cause of cellinjury, clear out necrotic cells and tissues damaged from the originalinsult and the inflammatory process, and to initiate tissue repair.(Ferrero-Miliani L, Nielsen O H, Andersen P S, Girardin S E; Nielsen;Andersen; Girardin (February 2007) Clin. Exp. Immunol. 147)

Inflammation is classified as either acute or chronic. Acuteinflammation is the initial response of the body to harmful stimuli andis achieved by the increased movement of plasma and leukocytes(especially granulocytes) from the blood into the injured tissues. Aseries of biochemical events propagates and matures the inflammatoryresponse, involving the local vascular system, the immune system, andvarious cells within the injured tissue.

Prolonged inflammation, known as chronic inflammation, is characterizedby simultaneous destruction and healing of the tissue from theinflammatory process. It leads to a progressive shift in the type ofcells present at the site of inflammation, such as mononuclear cells,and increases in systemic concentrations of cytokines such as TNF-α,IL-6, and CRP. (Petersen, A. M.; Pedersen, B. K. (2005). J Appl Physiol.98 (4): 1154-1162)

Many proteins are involved in inflammation. Any of them are susceptibleto genetic mutation which may impair or otherwise dysregulate theirnormal function and expression.

Methods of Treating Inflammatory Disease

Both small molecules and biologics are used to treat inflammatorydiseases. Most treatments, however, are largely palliative.

A clear unmet medical need remains to find treatments that canmechanistically reduce chronic inflammatory diseases.

Pathobiology of Fibrotic Disease

Fibrosis, or the accumulation of extracellular matrix molecules thatconstitute scar tissue, is a common result of tissue injury. Pulmonaryfibrosis, renal fibrosis, and hepatic cirrhosis are among the commonfibrotic diseases which altogether represent a large unmet medical need.(Friedman S L, Sheppard D, Duffield J S, Violette S. Sci Transl MedJanuary 9; 5(167)

Mechanisms of fibrogenesis include inflammatory as well as otherpathways and generally involve reorganization of the actin cytoskeletonof affected cells, including epithelial cells, fibroblasts, endothelialcells, and macrophages.

Actin filament assembly and actomyosin contraction are directed by theRho-associated coiled-coil forming protein kinase (ROCK) family ofserine/threonine kinases (ROCK1 and ROCK₂) and thus Rho is associatedwith fibrogenesis.

Tissue fibrosis is a leading cause of morbidity and mortality. 45% ofdeaths in the United States are attributable to fibrotic disorders.(Wynn T A. “Fibrotic Disease and the TH1/TH2 Paradigm.” Nat Rev Immunol2004 August: 4(8): 583-594.) Treatments are generally palliative.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lungscarring, short median survival, and limited therapeutic options,creating great need for new pharmacologic therapies. It is thought toresult from repetitive environmental injury to the lung epithelium.

Targeted Therapy of Cancer, Inflammatory, and Fibrotic Diseases

Targeted therapies are a cornerstone of what is also referred to asprecision medicine, a form of medicine that uses information about aperson's genes and proteins to prevent, diagnose, and treat disease.Such therapeutics are sometimes called “molecularly targeted drugs,”“molecularly targeted therapies,” or similar names. The process ofdiscovering them is often referred to as “rational drug design.”

A series of actions among molecules in a cell that leads to a certainend point or cell function is referred to as a molecular pathway.

Molecularly targeted drugs interact with a particular target molecule,or structurally related set of target molecules, in a pathway; thusmodulating the endpoint effect of that pathway, such as adisease-related process; and, thus, yielding a therapeutic benefit.

Molecularly targeted drugs may be small molecules or biologics, usuallyantibodies. They may be useful alone or in combinations with othertherapeutic agents and methods.

Because they target a particular molecule, or related set of molecules,and are usually designed to minimize their interactions with othermolecules, targeted therapeutics may have fewer adverse side effects.

Targeted cancer drugs block the growth and spread of cancer byinteracting with specific molecules or sets of structurally relatedmolecules (altogether, “molecular targets”) that are involved, broadlyspeaking, in the growth, progression, lack of suppression orelimination, or spread of cancer. Such molecular targets may includeproteins or genes involved in one or more cellular functions including,for example and without limitation, signal transduction, gene expressionmodulation, apoptosis induction or suppression, angiogenesis inhibition,or immune system modulation.

In some cases, the development of targeted cancer therapeutics involvesidentifying genes or proteins that are present in cancer cells but notnormal cells or that are more abundant or more highly stimulated incancer cells, especially if they are known to be involved in cancerprocesses, and then discovering agents that will interact with thosetargets and be associated with a desired therapeutic effect.

Targeted cancer therapies generally differ from standard cancerchemotherapy in several ways:

-   -   a. Targeted therapies are deliberately chosen or designed to        interact with their target(s), whereas many standard        chemotherapies were identified because they were found in        general to kill cells.    -   b. Targeted therapies are intended to act on specific molecular        targets that are associated with cancer, whereas most standard        chemotherapies act on all rapidly dividing normal and cancerous        cells. They may, however, also have known and sometime unknown        interactions with other molecules, so-called off-target effects.    -   c. Most targeted therapies are cytostatic (that is, they block        tumor cell proliferation), whereas standard chemotherapy agents        are usually cytotoxic (that is, they kill tumor cells). However,        some targeted therapies such as Antibody Drug Conjugates are        cytotoxic.

Targeted therapy monoclonal antibodies (mAbs) and targeted smallmolecules are being used as treatments for inflammatory diseases(Kotsovilis S, Andreakos E., Methods Mol Biol. 2014; 1060:37-59). Theyare used either as a monotherapy or in combination with otherconventional therapeutic modalities, particularly if the disease undertreatment is refractory to therapy using solely conventional techniques.

Some treatments for fibrotic disorders, such as idiopathic pulmonaryfibrosis, hepatic fibrosis, and systemic sclerosis, target inflammatorypathways.

The Ras GTPase Family

The Ras superfamily of proteins are small GTPases with substantial aminoacid sequence homology that act as signal transducers between cellsurface receptors and several intracellular signaling cascades. Thesemolecules are involved in the regulation of such essential cellularfunctions as cell survival, proliferation, motility, and cytoskeletalorganization (see Karnoub et al., Nat. Rev. Mol. Cell Biol., 9: 517-531(2008)).

Research has defined a number of subfamilies of the Ras superfamily,based largely on amino acid sequence homologies. These subfamilies areoften referred to in an abbreviated manner based on the most commonlystudied member of the class.

The GTP binding domains of one subfamily of the Ras superfamily havingsubstantial sequence homology is commonly referred to as the Ras familyor Ras.

There are four isoforms of Ras proteins, expressed from three differentgenes: H-Ras (Harvey sarcoma viral oncogene), N-Ras (neuroblastomaoncogene), and the splice variants K-Ras4A and K-Ras4B (Kirsten sarcomaviral oncogene) (see Karnoub et al., supra).

The GTP binding domains of another subfamily of the Ras superfamilyhaving substantial sequence homology, is commonly referred to as the Rhofamily and includes proteins and groups of proteins referred to as Rho,Rac and Cdc42.

Ras Function and Pathways

All Ras isoforms share sequence identity in all of the regions that areresponsible for GDP/GTP binding, GTPase activity, and effectorinteractions, suggesting a functional redundancy. However, studiesclearly demonstrate that each Ras isoform functions in a unique,different way from the other Ras proteins in normal physiologicalprocesses as well as in pathogenesis (Quinlan et al., Future Oncol., 5:105-116 (2009)).

Ras proteins cycle between ‘on’ and ‘off’ conformations that areconferred by the binding of GTP and GDP, respectively. Underphysiological conditions, the transition between these two states isregulated by guanine nucleotide exchange factors (GEFs), which promotethe activation of Ras proteins by stimulating the exchange of GDP forGTP exchange, and by GTPase-activating proteins (GAPs), which accelerateRas-mediated GTP hydrolysis to GDP.

Several cell surface receptors activate Ras, such as Receptor TyrosineKinases (RTKs), growth factor receptors, cytokine receptors andintegrins.

Once activated, Ras initiates signaling of the “MAPK pathway” (alsoreferred to as the Ras-RAF-MEK-MAPK/ERK pathway) that affects cellgrowth, differentiation, proliferation, apoptosis and migration. It isalso associated with other molecular pathways including phosphoinositide3-kinases (PI3Ks), Rac1 GEF, and the Ral-guanine nucleotide dissociationstimulator (GDS).

The MAPK pathway operates through a sequence of interactions amongkinases. Activated by Ras in the “on”, GTP bound, state, a MAPK kinasekinase (MAPK3), such as Raf, MLK, or TAK, phosphorylates and activates aMAPK kinase, such as MEK, which then phosphorylates and increases theactivity of one or more MAPKs, such as ERK1/2. PI3K is part of thePI3K/AKT/mTOR pathway regulating intracellular signaling important forseveral cellular functions such as survival, anti-apoptotic and cellcycle.

Ras Dysfunction Is Causally Associated with Important Diseases andDisease Processes

Ras and its downstream pathways, including MAPK, have been studiedextensively. They are causally associated with a range of diseases,including certain cancers, inflammatory disorders, Ras-associatedautoimmune leukoproliferative disorder, and certain Rasopathies.

There is more than one distinct route to aberrant Ras activationincluding mutational activation of Ras itself, excessive activation ofthe wild-type protein through upstream signaling, and loss of a GAPfunction that is required to terminate activity of the protein.

One million deaths per year are attributed in the literature tomutations in K-Ras alone. (Frank McCormick. “K-Ras protein as a drugtarget.” Journal of Molecular Medicine (Berlin) 2016: 94: 253-258)

Ras is well documented in the literature as an oncogene. Ras oncogenescan initiate cancer in model organisms. Microinjection studies withantibodies that block Ras activity or block specific mutant alleles ofRas; ablation of K-Ras in mouse models of lung adenocarcinoma orpancreas cancer; and ablation of H-Ras all lead to tumor regression inmouse models.

About 30% (Prior I A, Lewis P D, Mattos C. Cancer Res. 2012 May 15;72(10):2457-67) of human cancers have a mutated Ras protein with themost frequent mutations in residues G12, G13 and Q61. These oncogenicmutations result in impaired GTP hydrolysis and accumulation of Ras inthe GTP-bound state leading to increased activation of Ras-dependentdownstream effector pathways.

Table 1 summarizes recent data concerning the frequency of K-Ras andN-Ras mutations in an illustrative, but not exhaustive list, of humanmalignancies.

TABLE 1 Mutation Tumor Type Frequency K-Ras Pancreas 71% K-Ras Colon 35%K-Ras Small intestine 35% K-Ras Biliary tract 28% K-Ras Endometrium 22%K-Ras Lung 20% N-Ras Skin (melanoma) 20% K-Ras Cervix 19% K-Ras Urinarytract 16% Stephen A G, Esposito D, Bagni R K, McCormick F. Cancer Cell.2014 Mar 17; 25(3): 272-81.

Ras mutants, and in some cases Ras over-activation, are associated inthe literature with a wide range of significant cancer associatedprocesses including: cell proliferation, DNA checkpoint integrity,replicative stress related clonal selection, suppression of apoptosis,metabolic reprogramming, autophagy, microenvironment remodeling, immuneresponse evasion, and metastatic processes. The detailed mechanisms,interdependencies, and frequency of these effects across different tumortypes and stages of cancer development remain to be elucidatedcomprehensively.

Proliferative effects associated in the literature with oncogenic Rasinclude transcriptional upregulation of growth factors; upregulation ofgrowth factor receptor expression; upregulation of integrins thatpromote proliferation and downregulation of those associated withcellular quiescence; upregulation of transcription factors required forcell cycle entry; acceleration through cell cycle transitions;downregulation of anti-proliferative TGFβ signaling; and the suppressionof cyclin-dependent kinase inhibitors.

MAPK signaling has been shown to enhance programmed death-ligand 1(PD-L1) expression in KRas mutant lung cancer cells and thus Rasmutations are associated with the suppression of immune responses tocancer. (Sumimoto et al., PLOS One 2016 Nov. 15;DOI:10.1371/journal.pone.0166626) Anti-PD-1 and anti-PD-L1 monoclonalantibodies have demonstrated clinical activity against tumors includingnon-small cell lung cancers.

Ras is also implicated through the MAPK pathways as a cause of a rangeof pathological inflammatory conditions. In addition to ERK1/2, theMAPKs ERK5, c-Jun N-terminal kinases (JNKs) and p38 isoforms have beenshown to be implicated in inflammatory response. (Huang, et al. 2010,Protein Cell, 1(3), 218-226)

Ras is causally associated with inflammatory diseases including thefollowing: rheumatoid arthritis (Abreu J R, de Launay D, Sanders M E,Grabiec A M, Sande van de M G, Tak P P, Reedquist K A: The Ras guaninenucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3production in rheumatoid arthritis synovial tissue. Arthritis Res Ther.2009, 11: R121-10.1186/ar2785), which is the most common cause ofdisability (Hootman J M, Brault M W, Helmick C G, Theis K A, Armour B S.Prevalence and most common causes of disability among adults—UnitedStates 2005, MMWR, 2009, 58(16):421-6); atherosclerosis (Fonarow G(2003), Cleve. Clin. J. Med. 70: 431-434); inflammatory bowel disease(IBD), such as Crohn's disease (Ignacio C S, Sandvik A K, Bruland T,Andreu-Ballester J C, J. Crohns Colitis, 2017 Mar. 16. doi: 10);ulcerative colitis, spondyloarthropathies, idiopathic pulmonaryfibrosis, juvenile arthritis, psoriasis, psoriatic arthritis, andothers.

Ras has been causally associated with Ras-associated autoimmuneleukoproliferative disorder, a nonmalignant clinical syndrome initiallyidentified in a subset of putative autoimmune lymphoproliferativesyndrome (ALPS) patients. (Katherin Calvo, et al. “JMML and RALD(Ras-associated autoimmune leukoproliferative disorder): common geneticetiology yet clinically distinct entities” Blood, 2015 Apr. 30; 125(18):2753-2758)

Aberrant Ras signaling is causally implicated in the family ofRasopathies including neurofibromatosis type 1, Noonan's syndrome, andCostello syndrome.

Ras as a Therapeutic Molecular Target

Interference with Ras superfamily member signaling in cell based andanimal models of the aforementioned diseases modulates diseaseprocesses.

Ras superfamily proteins, and particularly Ras and downstream pathwayelements, have thus long been discussed as theoretical molecular targetsfor the development of targeted therapeutics. In theory, a moleculecould serve as a therapeutic agent in diseases associated with aberrantRas signaling if it could disrupt such Ras signaling.

In theory, it was recognized that a mechanism for downregulatingaberrant Ras signaling could be to interfere with one or more steps inthe Ras signaling process involving GTP binding in a manner that leftthe GTP in other than an “on” configuration. However, while this was aconcept in theory, based on two widely accepted findings, it has alsolong been accepted by the scientific community that it would not bepossible to achieve.

GTP and GDP had been found to bind to the GTP binding domain of Ras withsingle to double digit picomolar affinities.

The cellular concentration of GTP had been found to be substantially inexcess of this range.

The widely accepted findings concerning the single to double digitpicomolar range of affinities of GTP and GDP for the Ras GTP bindingdomain were determined by kinetic and filter binding measurementsbetween Ras and radiolabeled GDP and GTP (Feuerstein J, Kalbitzer H R,John J, Goody R S, Wittinghofer A. Eur. J. Biochem., 1987 Jan. 2,162(1):49-55; and John J, Sohmen R, Feuerstein J, Linke R, WittinghoferA, Goody R S. Biochemistry, 1990 Jun. 26, 29(25):6058-65).

Consistent with these findings, and often citing them, the GTP bindingdomain of Ras has widely been accepted and reported in preeminentjournal editorials, reviews, and research papers to be “undruggable.”(Papke B, Der C J., Science, 2017 Mar. 17, 355(6330):1158-1163; StephenA G, Esposito D, Bagni R K, McCormick F, Cancer Cell, 2014 Mar. 17,25(3):272-81; and Ostrem J M, Shokat K M, Nat. Rev. Drug Discov., 2016Nov. 15(11):771-785)

Accordingly, research concerning targeted Ras therapeutics has focusedon domains of the Ras protein other than the GTP binding site. Theseinclude, for example, farnesyltransferase inhibitors (FTIs) that preventRas attachment to the inner side of the plasma membrane, and moleculesthat compete with the interaction of Ras with the exchange factor SOS ordownstream effectors.

Thus, it has been thought that a molecule could not be developed tocompete with GTP binding to the GTP binding domain of Ras. Compoundsthat do so, however, would fill a need in the field.

The Rho Family Function and Pathways

The Rho subfamily of the Ras superfamily currently includesapproximately 22 proteins most of which scientists commonly divide intosubgroups including those referred to as Cdc42, Rac, and Rho. (BoureuxA, Vignal E, Faure S, Fort P (2007). “Evolution of the Rho family ofras-like GTPases in eukaryotes”. Mol Biol Evol 24 (1): 203-16).

The three most commonly studied members of the Rho subfamily have beenCdc42, Rac1, and RhoA,

The Cdc42 group includes Cdc42, TC10, TCL, Chip, and Wrch-1.

The Rac group includes Rac1 Rac2, Rac3, and RhoG.

The RhoA group includes RhoA, RhoB, and RhoC.

Other Rho subfamily GTPases not included in the Cdc42. Rac, or Rhogroups include RhoE/Rnd3, RhoH/TTF, Rif, RhoBTB1, RhoBTB2, Miro-1,Miro-2, RhoD, Rnd1, and Rnd2.

Like other Ras superfamily proteins, the Rho subfamily GTPases cyclebetween ‘on’ and ‘off’ conformations that are conferred by the bindingof GTP and GDP, respectively. Under physiological conditions, thetransition between these two states is regulated by guanine nucleotideexchange factors (GEFs), which promote the activation of Rho subfamilyproteins by stimulating the release of GDP and the binding of GTP, andby GTPase-activating proteins (GAPs), which accelerate Rho subfamilymember-mediated GTP hydrolysis to GDP. Guanine nucleotide dissociationinhibitors (GDIs) proteins form a large complex with the Rho protein,helping to prevent diffusion within the membrane and into the cytosoland thus acting as an anchor and allowing tight spatial control of Rhoactivation.

The Rho subfamily members are intracellular proteins that affect a largenumber of downstream pathways broadly involving cytoskeletonorganization, cell polarity, migration, transcription and proliferation,and, more particularly, membrane and vesicular trafficking, cellcycling, microtubule stability, actin membrane linkages, actinpolymerization, myosin phosphorylation, API dependent gene expression,cell adhesion, cell contractility, cell adhesion, and MTOC orientation.(Martin Schwartz. “Rho Signalling at a Glance.” Journal of Cell Science.2004: (117: pp. 5457-5458) and (Bustelo X R, Sauzeau V, Berenjeno I M(2007). “GTP-binding proteins of the Rho/Rac family: regulation,effectors and functions in vivo” BioEssays. 29 (4): 356-370).

Rho Family Dysfunction Is Causally Associated with Important Diseases

Rho subfamily GTPases have been reported to contribute to most steps ofcancer initiation and progression including the acquisition of unlimitedproliferation potential, survival and evasion from apoptosis,angiogenesis, tissue invasion, motility, and the establishment ofmetastases. (Matteo Parri and Paolo Chiarugi. “Rac and Rho GTPases inCancer Cell Motility Control.” Cell Communication and Signalling. 2010(8:23))

High Rho subfamily protein levels are frequently associated with humantumors. High RhoA levels have been associated with human liver, skin,colon, ovarian, bladder, gastric, esophageal squamous cell, testicular,and breast cancer. High Rho B, C, or H levels have been associated withbreast, squamous cell, pancreatic, breast, liver, ovarian, head andneck, prostate, non-small cell lung, and gastric cancers and melanomametastase. High Rac1 levels have been associated with human testicular,gastric, breast, and squamous cell cancers. High Rac2 or Rac3 have beenassociated with breast colon, head and neck, and squamous cell cancers.(Matteo Parri and Paolo Chiarugi. “Rac and Rho GTPases in Cancer CellMotility Control.” Cell Communication and Signalling. 2010 (8:23).Gain-of-function mutations such as P29S of Rac1 were detected inmelanoma, breast, head and neck cancers (Alan J K, Lundquist E A.Mutationally activated Rho GTPases in cancer. Small GTPases. 2013July-September; 4(3):159-63)

Unlike Ras proteins, which are frequently mutated in cancer (around30%), Rho subfamily proteins themselves are generally not found to bemutated in cancer. Rather, aberrant activity of Rho subfamily proteinsin cancer appears to occur by overexpression of these proteins or byaberrant regulation of molecules that control their activity, such asactivation or overexpression of GEFs and inactivation or loss of GAPs orGDIs (Alan J K, Lundquist E A. Mutationally activated Rho GTPases incancer. Small GTPases. 2013 July-September; 4(3):159-63).

Interactions between Rac and Rho proteins are believed to modulatecertain forms of mesenchymal and amoeboid cell movement associated withcancer.

Rho subfamily associated kinases (ROCK1 and ROCK₂) are implicated asmediators of multiple profibrotic processes including those associatedwith idiopathic pulmonary fibrosis. (Knipe R S, Tager E M, and Liao J K.“The Rho kinases: critical mediators of multiple profibrotic processesand rational targets for new therapies for pulmonary fibrosis.”Pharmacol Rev. 2015 67(1):103-17.)

Rho Family Members as Therapeutic Molecular Targets

Given their roles in disease processes, Rho subfamily members have beenidentified as potential Therapeutic Molecular Targets.

Rho subfamily members have been identified as potential TherapeuticMolecular Targets in cancer.

Rho subfamily members have been identified as potential TherapeuticMolecular Targets in fibrotic disease.

3. SUMMARY

For the first time, the affinity of GTP for the GTP binding domain ofK-Ras utilizing a Scintillation Proximity Assay (SPA) and MicroScaleThermophoresis (MST) has been measured and disclosed herein. Thesemethods were not available when Wittinghofer and colleagues (referencedabove) undertook their studies.

In SPA and MST studies, it was found and is disclosed herein that theaffinity of GTP for the K-Ras GTP binding domain across wild type andmutant K-Ras is in the range of 100-465 nanomolar. This therefore led tothe novel, unanticipated conclusion that compounds such as smallmolecules could be discovered that would bind to a Ras GTP bindingdomain and compete with the binding of GTP to Ras.

Provided herein is a novel cell-free assay for the identification ofsmall molecules that bind to the GTP binding domain and compete with GTPbinding to, for example, wild-type KRas, KRas G12D mutant, KRas G12Cmutant, KRas Q61H mutant, KRas G12D/Q61H double mutant, KRas G12C/Q61Hdouble mutant, Rac1 and RhoA proteins.

Utilizing this assay as a screening and analytical tool, over 1000 smallmolecules are provided that bind competitively with GTP to a Ras GTPbinding domain, thereby confirming the significance of the novel andunanticipated binding affinity findings. Provided herein is a method oftesting the affinity of a compound for a Ras GTP binding domaincomprising the novel assay.

Utilizing this assay, it was also demonstrated that over 1000 smallmolecules provided herein also bind competitively with GTP to both Racand Rho GTPase binding domains. Provided herein is a method of testingthe affinity of a compound for Rac and Rho GTP binding domainscomprising the novel assay.

It is also demonstrated herein in cell-based assays that certain ofthese molecules inhibit activation of the MAPK pathway and downregulatethe proliferation of different human tumors.

It is further demonstrated herein in cell-based assays that certain ofthese molecules downregulate the excretion of inflammatory cytokines.

It is also demonstrated herein in cell-based assays that certain ofthese molecules inhibit activation of the MAPK pathway and downregulatethe proliferation of different human tumors.

It is further demonstrated herein in cell-based assays that certain ofthese molecules downregulate the excretion of inflammatory cytokines.

It is also demonstrated herein in cell-based assays that certain ofthese molecules inhibit activation of the MAPK pathway and downregulatethe proliferation of different human tumors.

It is further demonstrated herein in cell-based assays that certain ofthese molecules downregulate the excretion of inflammatory cytokines.

It has also been discovered and disclosed herein that certain aminoacids in the Ras GTP binding domain enable the heretofore unanticipatedcompetitive binding to that domain between compounds, such as smallmolecules, and GTP. They include the following amino acids: Ala11,Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31,Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147, and also Mg202 which is required for GTPbinding. They also include the amino acid Gln61.

It has also been discovered and disclosed herein that certain aminoacids in the Rac1 GTP binding domain enable the heretofore unanticipatedcompetitive binding to that domain between compounds, such as smallmolecules, and GTP. They include the following amino acids: Gly12,Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36,Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, and also Mg202which is required for GTP binding.

It has also been discovered and disclosed herein that certain aminoacids in the RhoA GTP binding domain enable the heretofore unanticipatedcompetitive binding to that domain between compounds, such as smallmolecules, and GTP. They include the following amino acids: Gly14,Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34,Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, and also Mg202 whichis required for GTP binding.

Therefore, provided herein is a method of inhibiting the function ofRas, comprising administering to a subject a compound whichcompetitively binds to a Ras GTP binding domain. In one embodiment, thecompound for use in the method has a binding affinity (K_(d)) to a RasGTP binding domain of less than 10 μM. In one embodiment, the compoundfor use in the method has a binding affinity (K_(d)) to a Ras GTPbinding domain of less than 1 μM. In one embodiment, the compound foruse in the method has a binding affinity (K_(d)) to a Ras GTP bindingdomain of less than 500 nM. In one embodiment, the compound for use inthe method has a binding affinity (K_(d)) to a Ras GTP binding domain ofless than 465 nM. In one embodiment, the compound for use in the methodhas a binding affinity (K_(d)) to a Ras GTP binding domain of less than270 nM. In one embodiment, the compound for use in the method has abinding affinity (K_(d)) to a Ras GTP binding domain of less than 200nM. In one embodiment, the compound for use in the method has a bindingaffinity (K_(d)) to a Ras GTP binding domain of less than 150 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Ras GTP binding domain of less than 100 nM. In oneembodiment, the method of inhibiting the function of Ras, comprisesadministering to a subject a compound which binds to one or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120,Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain with abinding affinity (K_(d)) of less than 465 nM. In one embodiment, themethod of inhibiting the function of Ras, comprises administering to asubject a compound which binds to one or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain with a binding affinity(K_(d)) of less than 270 nM. In one embodiment, the method of inhibitingthe function of Ras, comprises administering to a subject a compoundwhich binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in ahighly conserved Ras GTP binding domain with a binding affinity (K_(d))of less than 10 μM. In one embodiment, the method of inhibiting thefunction of Ras, comprises administering to a subject a compound whichbinds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in aRas GTP binding domain with a binding affinity (K_(d)) of less than 465nM. In one embodiment, the method of inhibiting the function of Ras,comprises administering to a subject a compound which binds to one ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain with a binding affinity (K_(d)) of less than 270 nM. In oneembodiment, the method of inhibiting the function of Ras, comprisesadministering to a subject a compound which binds to one or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln 61, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a highly conserved Ras GTPbinding domain with a binding affinity (K_(d)) of less than 10 μM.

In an assay described herein, e.g., a cell-free assay, the compound foruse in the method inhibits Ras and has an IC₅₀ value of less than 10 μM.In one embodiment, the compound for use in the method inhibits Ras andhas an IC₅₀ value of less than 1 μM. In one embodiment, the compound foruse in the method inhibits Ras and has an IC₅₀ value of less than 500nM. In one embodiment, the compound for use in the method inhibits Rasand has an IC₅₀ value of less than 465 nM. In one embodiment, thecompound for use in the method inhibits Ras and has an IC₅₀ value ofless than 270 nM. In one embodiment, the compound for use in the methodinhibits Ras and has an IC₅₀ value of less than 200 nM. In oneembodiment, the compound for use in the method inhibits Ras and has anIC₅₀ value of less than 150 nM. In one embodiment, the compound for usein the method inhibits Ras and has an IC₅₀ value of less than 100 nM. Inone embodiment, the compound for use in the method inhibits Ras withgreater than 25% inhibition at 20 μM. In one embodiment, the compoundfor use in the method inhibits Ras with greater than 50% inhibition at20 μM. In one embodiment, the compound for use in the method inhibitsRas with greater than 75% inhibition at 20 μM. In one embodiment, thecompound for use in the method inhibits Ras with greater than 80%inhibition at 20 μM. In one embodiment, the compound for use in themethod inhibits Ras with greater than 85% inhibition at 20 μM. In oneembodiment, the compound for use in the method inhibits Ras with greaterthan 90% inhibition at 20 μM. In one embodiment, the compound for use inthe method inhibits Ras with greater than 95% inhibition at 20 μM. Inone embodiment, the compound for use in the method inhibits Ras withgreater than 99% inhibition at 20 μM. In one embodiment, the method ofinhibiting the function of Ras, comprises administering to a subject acompound which binds to one or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 orMg202 in a Ras GTP binding domain and inhibits Ras with a correspondingIC₅₀ value of less than 465 nM. In one embodiment, the method ofinhibiting the function of Ras, comprises administering to a subject acompound which binds to one or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 orMg202 in a Ras GTP binding domain and inhibits Ras with a correspondingIC₅₀ value of less than 270 nM. In one embodiment, the method ofinhibiting the function of Ras, comprises administering to a subject acompound which binds to one or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 orMg202 in a highly conserved Ras GTP binding domain and inhibits Ras witha corresponding IC₅₀ value of less than 10 μM. In one embodiment, themethod of inhibiting the function of Ras, comprises administering to asubject a compound which binds to one or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a highly conserved Ras GTP binding domain andinhibits Ras with greater than 50% inhibition at 20 μM. In oneembodiment, the method of inhibiting the function of Ras, comprisesadministering to a subject a compound which binds to one or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain andinhibits Ras with a corresponding IC₅₀ value of less than 465 nM. In oneembodiment, the method of inhibiting the function of Ras, comprisesadministering to a subject a compound which binds to one or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain andinhibits Ras with a corresponding IC₅₀ value of less than 270 nM. In oneembodiment, the method of inhibiting the function of Ras, comprisesadministering to a subject a compound which binds to one or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a highly conserved Ras GTPbinding domain and inhibits Ras with a corresponding IC₅₀ value of lessthan 10 μM. In one embodiment, the method of inhibiting the function ofRas, comprises administering to a subject a compound which binds to oneor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a highlyconserved Ras GTP binding domain and inhibits Ras with greater than 50%inhibition at 20 μM.

In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS;KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12;REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In one embodiment, theRas is HRAS, KRAS or NRAS. In one embodiment, the Ras is HRAS. In oneembodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. Inanother embodiment, the Ras is a mutant form of a Ras described herein.

Also provided herein is a method of inhibiting the function of Rho,comprising administering to a subject a compound which competitivelybinds to a Rho GTP binding domain. In one embodiment, the compound foruse in the method has a binding affinity (K_(d)) to a Rho GTP bindingdomain of less than 10 μM. In one embodiment, the compound for use inthe method has a binding affinity (K_(d)) to a Rho GTP binding domain ofless than 1 μM. In one embodiment, the compound for use in the methodhas a binding affinity (K_(d)) to a Rho GTP binding domain of less than500 nM. In one embodiment, the compound for use in the method has abinding affinity (K_(d)) to a Rho GTP binding domain of less than 270nM. In one embodiment, the compound for use in the method has a bindingaffinity (K_(d)) to a Rho GTP binding domain of less than 200 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Rho GTP binding domain of less than 150 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Rho GTP binding domain of less than 130 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Rho GTP binding domain of less than 100 nM. In oneembodiment, the method of inhibiting the function of Rho, comprisesadministering to a subject a compound which binds to one or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain with a binding affinity (K_(d)) of less than 270nM. In one embodiment, the method of inhibiting the function of Rho,comprises administering to a subject a compound which binds to one ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain with a binding affinity (K_(d)) ofless than 130 nM. In one embodiment, the method of inhibiting thefunction of Rho, comprises administering to a subject a compound whichbinds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20,Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120,Lys162 or Mg202 in a highly conserved Rho GTP binding domain with abinding affinity (K_(d)) of less than 10 μM.

In an assay described herein, e.g., a cell-free assay, the compound foruse in the method inhibits Rho and has an IC₅₀ value of less than 10 μM.In one embodiment, the compound for use in the method inhibits Rho andhas an IC₅₀ value of less than 1 μM. In one embodiment, the compound foruse in the method inhibits Rho and has an IC₅₀ value of less than 500nM. In one embodiment, the compound for use in the method inhibits Rhoand has an IC₅₀ value of less than 270 nM. In one embodiment, thecompound for use in the method inhibits Rho and has an IC₅₀ value ofless than 200 nM. In one embodiment, the compound for use in the methodinhibits Rho and has an IC₅₀ value of less than 150 nM. In oneembodiment, the compound for use in the method inhibits Rho and has anIC₅₀ value of less than 130 nM. In one embodiment, the compound for usein the method inhibits Rho and has an IC₅₀ value of less than 100 nM. Inone embodiment, the compound for use in the method inhibits Rho withgreater than 25% inhibition at 20 μM. In one embodiment, the compoundfor use in the method inhibits Rho with greater than 50% inhibition at20 μM. In one embodiment, the compound for use in the method inhibitsRho with greater than 75% inhibition at 20 μM. In one embodiment, thecompound for use in the method inhibits Rho with greater than 80%inhibition at 20 μM. In one embodiment, the compound for use in themethod inhibits Rho with greater than 85% inhibition at 20 μM. In oneembodiment, the compound for use in the method inhibits Rho with greaterthan 90% inhibition at 20 μM. In one embodiment, the compound for use inthe method inhibits Rho with greater than 95% inhibition at 20 μM. Inone embodiment, the compound for use in the method inhibits Rho withgreater than 99% inhibition at 20 μM. In one embodiment, the method ofinhibiting the function of Rho, comprises administering to a subject acompound which binds to one or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain andinhibits Rho with a corresponding IC₅₀ value of less than 270 nM. In oneembodiment, the method of inhibiting the function of Rho, comprisesadministering to a subject a compound which binds to one or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain and inhibits Rho with a corresponding IC₅₀ valueof less than 130 nM. In one embodiment, the method of inhibiting thefunction of Rho, comprises administering to a subject a compound whichbinds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20,Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120,Lys162 or Mg202 in a highly conserved Rho GTP binding domain andinhibits Rho with a corresponding IC₅₀ value of less than 10 μM. In oneembodiment, the method of inhibiting the function of Rho, comprisesadministering to a subject a compound which binds to one or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in ahighly conserved Rho GTP binding domain and inhibits Rho with greaterthan 50% inhibition at 20 μM.

In one embodiment, the Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3;RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3;RAC1; RAC2; RAC3 or CDC42. In one embodiment, the Rho is RHOA. Inanother embodiment, the Rho is a mutant form of a Rho described herein.

Also provided herein is a method of inhibiting the function of Rac,comprising administering to a subject a compound which competitivelybinds to a Rac GTP binding domain. In one embodiment, the compound foruse in the method has a binding affinity (K_(d)) to a Rac GTP bindingdomain of less than 10 μM. In one embodiment, the compound for use inthe method has a binding affinity (K_(d)) to a Rac GTP binding domain ofless than 1 μM. In one embodiment, the compound for use in the methodhas a binding affinity (K_(d)) to a Rac GTP binding domain of less than500 nM. In one embodiment, the compound for use in the method has abinding affinity (K_(d)) to a Rac GTP binding domain of less than 270nM. In one embodiment, the compound for use in the method has a bindingaffinity (K_(d)) to a Rac GTP binding domain of less than 200 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Rac GTP binding domain of less than 170 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Rac GTP binding domain of less than 150 nM. In oneembodiment, the compound for use in the method has a binding affinity(K_(d)) to a Rac GTP binding domain of less than 100 nM. In oneembodiment, the method of inhibiting the function of Rac, comprisesadministering to a subject a compound which binds to one or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain with a binding affinity (K_(d)) of less than270 nM. In one embodiment, the method of inhibiting the function of Rac,comprises administering to a subject a compound which binds to one ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a Rac GTP binding domain with a binding affinity (K_(d)) ofless than 170 nM. In one embodiment, the method of inhibiting thefunction of Rac, comprises administering to a subject a compound whichbinds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19,Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119,Cys157, Ala159, or Mg202 in a highly conserved Rac GTP binding domainwith a binding affinity (K_(d)) of less than 10 μM.

In an assay described herein, e.g., a cell-free assay, the compound foruse in the method inhibits Rac and has an IC₅₀ value of less than 10 μM.In one embodiment, the compound for use in the method inhibits Rac andhas an IC₅₀ value of less than 1 μM. In one embodiment, the compound foruse in the method inhibits Rac and has an IC₅₀ value of less than 500nM. In one embodiment, the compound for use in the method inhibits Racand has an IC₅₀ value of less than 270 nM. In one embodiment, thecompound for use in the method inhibits Rac and has an IC₅₀ value ofless than 200 nM. In one embodiment, the compound for use in the methodinhibits Rac and has an IC₅₀ value of less than 170 nM. In oneembodiment, the compound for use in the method inhibits Rac and has anIC₅₀ value of less than 150 nM. In one embodiment, the compound for usein the method inhibits Rac and has an IC₅₀ value of less than 100 nM. Inone embodiment, the compound for use in the method inhibits Rac withgreater than 25% inhibition at 20 μM. In one embodiment, the compoundfor use in the method inhibits Rac with greater than 50% inhibition at20 μM. In one embodiment, the compound for use in the method inhibitsRac with greater than 75% inhibition at 20 μM. In one embodiment, thecompound for use in the method inhibits Rac with greater than 80%inhibition at 20 μM. In one embodiment, the compound for use in themethod inhibits Rac with greater than 85% inhibition at 20 μM. In oneembodiment, the compound for use in the method inhibits Rac with greaterthan 90% inhibition at 20 μM. In one embodiment, the compound for use inthe method inhibits Rac with greater than 95% inhibition at 20 μM. Inone embodiment, the compound for use in the method inhibits Rac withgreater than 99% inhibition at 20 μM. In one embodiment, the method ofinhibiting the function of Rac, comprises administering to a subject acompound which binds to one or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Ras GTP binding domain andinhibits Rac with a corresponding IC₅₀ value of less than 270 nM. In oneembodiment, the method of inhibiting the function of Rac, comprisesadministering to a subject a compound which binds to one or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain and inhibits Rac with a corresponding IC₅₀value of less than 270 nM. In one embodiment, the method of inhibitingthe function of Rac, comprises administering to a subject a compoundwhich binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Ras GTP binding domain andinhibits Rac with a corresponding IC₅₀ value of less than 170 nM. In oneembodiment, the method of inhibiting the function of Rac, comprisesadministering to a subject a compound which binds to one or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain and inhibits Rac with a corresponding IC₅₀value of less than 170 nM. In one embodiment, the method of inhibitingthe function of Rac, comprises administering to a subject a compoundwhich binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a highly conserved Rac GTP bindingdomain and inhibits Rac with a corresponding IC₅₀ value of less than 10μM. In one embodiment, the method of inhibiting the function of Rac,comprises administering to a subject a compound which binds to one ormore of Gly12, Ala 13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a highly conserved Rac GTP binding domain and inhibits Rho withgreater than 99% inhibition at 20 μM.

In one embodiment, the Rho is Rac. In one embodiment the Rac is RAC1;RAC2; RAC3 or RHOG. In one embodiment, the Rac is RAC1. In anotherembodiment, the Rac is a mutant form of a Rac described herein.

In one embodiment, provided herein is a method of treating or preventingcancer by administering a compound that inhibits the binding of GTP tothe GTP binding domain of one or more members of the Ras superfamily. Inone embodiment, provided herein is a method of treating or preventinginflammation by administering a compound that inhibits the binding ofGTP to the GTP binding domain of one or more members of the Rassuperfamily. In one embodiment, provided herein is a method of treatingor preventing a rasopathy by administering a compound that inhibits thebinding of GTP to the GTP binding domain of one or more members of theRas superfamily. In one embodiment, provided herein is a method oftreating or preventing fibrotic disease by administering a compound thatinhibits the binding of GTP to the GTP binding domain of one or moremembers of the Ras superfamily. In one embodiment, provided herein is amethod of treating or preventing cancer by administering a compound thatinhibits the binding of GTP to a Ras GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammation by administering a compound that inhibits the binding ofGTP to a Ras GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy by administering a compoundthat inhibits the binding of GTP to a Ras GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder by administering acompound that inhibits the binding of GTP to a Ras GTP binding domain.In one embodiment, provided herein is a method of treating or preventingfibrotic disease by administering a compound that inhibits the bindingof GTP to a Ras GTP binding domain. In one embodiment, provided hereinis a method of treating or preventing cancer by administering a compoundthat inhibits the binding of GTP to a Rho GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammation by administering a compound that inhibits the binding ofGTP to a Rho GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy by administering a compoundthat inhibits the binding of GTP to a Rho GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease by administering a compound that inhibits the bindingof GTP to a Rho GTP binding domain. In one embodiment, provided hereinis a method of treating or preventing cancer by administering a compoundthat inhibits the binding of GTP to a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammation by administering a compound that inhibits the binding ofGTP to a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy by administering a compoundthat inhibits the binding of GTP to a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease by administering a compound that inhibits the bindingof GTP to a Rac GTP binding domain.

Provided herein are compounds which bind to a Ras GTP binding domain andcompete with the binding of GTP to Ras. In one embodiment, the compoundsalso inhibit phosphorylation of MAPK, in particular MAPK1/2, cellularproliferation, secretion of IL-6 or TNF-α cytokines. The compoundsprovided herein are therefore useful in compositions and methods oftreating cancer, inflammatory diseases, Ras-associated autoimmuneleukoproliferative disorder and rasopathies.

Provided herein are compounds which bind to a Rac GTP binding domain andcompete with the binding of GTP to Rac. In one embodiment, the compoundsalso inhibit the MAPK signaling pathway. In one embodiment, thecompounds also inhibit the ROCK signaling pathway. The compoundsprovided herein are therefore useful in compositions and methods oftreating cancer, inflammatory diseases and fibrotic disease.

Provided herein are compounds which bind to a Rho GTP binding domain andcompete with the binding of GTP to Rho. In one embodiment, the compoundsalso inhibit the MAPK signaling pathway. In one embodiment, thecompounds also inhibit the ROCK signaling pathway. The compoundsprovided herein are therefore useful in compositions and methods oftreating cancer, inflammatory diseases and fibrotic disease.

In one embodiment, the compounds provided herein inhibit GTP binding toone or more members of the Ras superfamily. In one embodiment, thecompounds provided herein inhibit GTP binding to Ras. In one embodiment,the compounds provided herein inhibit GTP binding to Rho. In oneembodiment, the compounds provided herein inhibit GTP binding to Rac. Inone embodiment, the compounds provided herein inhibit GTP binding to Rasand Rho. In one embodiment, the compounds provided herein inhibit GTPbinding to Ras and Rac. In one embodiment, the compounds provided hereininhibit GTP binding to Rho and Rac. In one embodiment, the compoundsprovided herein inhibit GTP binding to Ras, Rho and Rac.

In one embodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 2000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1500 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1250 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 665 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 500 daltons. In anotherembodiment, the compound for use in the methods and compositionsprovided herein contains an oxadiazole, thiadiazole or triazole moiety.In another embodiment, the compound for use in the methods andcompositions provided herein contains a 1,2,4-oxadiazole,1,2,4-thiadiazole, 1,2,4-triazole, 2-acylaminothiazole,2-(pyridine-2-yl)pyrimidine-4-amine, 2-(pyridine-2-yl)pyrimidine-4-ol,2-(pyridine-2-yl)pyrimidine-4-(1H)-one,2-(pyridin-2-yl)pyrimidin-4(3H)-one,2-(pyridin-2-yl)pyrimidin-4(1H)-imine or2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, thecompound for use in the methods and compositions provided hereincontains a 2-(pyridin-2-yl)pyrimidine-4-amine,2-(pyridin-2-yl)pyrimidine-4-ol, 2-(pyridin-2-yl)pyrimidine-4-(1H)-one,2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one,2-(imidazol-2-yl)pyrimidin-4(1H)-one,2-(imidazol-2-yl)pyrimidin-4-amine,2-(imidazol-2-yl)pyrimidin-4(3H)-imine,2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol,2-(imidazol-4-yl)pyrimidin-4(3H)-one,2-(imidazol-4-yl)pyrimidin-4(1H)-one,2-(imidazol-4-yl)pyrimidin-4-amine,2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a crystal structure for GDP bound to the GTP binding siteof KRas (PDB code: 4 epr).

FIG. 2 depicts a compound disclosed herein binding to the guanosinebinding region of the GTP binding site of KRas as determined throughmolecular modeling of a compound disclosed herein with KRas crystalstructure PDB code: 4epr.

FIG. 3 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of KRas as determined through molecular modelingof a compound disclosed herein with KRas crystal structure PDB code:4epr.

FIG. 4 depicts a compound disclosed herein binding to the guanosinebinding region of the alternative Tyr32 conformation in the GTP bindingsite of KRas as determined through molecular modeling of a compounddisclosed herein with KRas crystal structure PDB code: 3 gft.

FIG. 5 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3 gft.

FIG. 6 depicts a compound disclosed herein binding to the guanosinebinding region of the GTP binding site of KRas as determined throughmolecular modeling of a compound disclosed herein with KRas crystalstructure PDB code: 4epr.

FIG. 7 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of KRas as determined through molecular modelingof a compound disclosed herein with KRas crystal structure PDB code:4epr.

FIG. 8 depicts a compound disclosed herein binding to the guanosinebinding region of the alternative Tyr32 conformation in the GTP bindingsite of KRas as determined through molecular modeling of a compounddisclosed herein with KRas crystal structure PDB code: 3gft.

FIG. 9 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft.

FIG. 10 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft.

FIG. 11 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft.

FIG. 12 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft.

FIG. 13 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rac-1 as determined through molecularmodeling of a compound disclosed herein with Rac-1 crystal structure PDBcode: 2p2l.

FIG. 14 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rac-1 as determined through molecularmodeling of a compound disclosed herein with Rac-1 crystal structure PDBcode: 2p2l.

FIG. 15 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rac-1 as determined through molecularmodeling of a compound disclosed herein with Rac-1 crystal structure PDBcode: 2p2l.

FIG. 16 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rho-A as determined through molecularmodeling of a compound disclosed herein with Rho-A crystal structure PDBcode: 5hpy.

FIG. 17 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rho-A as determined through molecularmodeling of a compound disclosed herein with Rho-A crystal structure PDBcode: 5hpy.

FIG. 18 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rho-A as determined through molecularmodeling of a compound disclosed herein with Rho-A crystal structure PDBcode: 5hpy.

5. DETAILED DESCRIPTION

5.1. Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

The singular forms “a,” “an,” and “the” include plural references,unless the context clearly dictates otherwise.

As used herein “subject” is an animal, such as a mammal, includinghuman, such as a patient.

As used herein, biological activity refers to the in vivo activities ofa compound or physiological responses that result upon in vivoadministration of a compound, composition or other mixture. Biologicalactivity, thus, encompasses therapeutic effects and pharmacokineticbehavior of such compounds, compositions and mixtures. Biologicalactivities can be observed in in vitro systems designed to test for suchactivities.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude, but are not limited to, salts, esters, enol ethers, enolesters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids,bases, clathrates, solvates or hydrates thereof. Such derivatives may bereadily prepared by those of skill in this art using known methods forsuch derivatization. The compounds produced may be administered toanimals or humans without substantial toxic effects and either arepharmaceutically active or are prodrugs. Pharmaceutically acceptablesalts include, but are not limited to, amine salts, such as but notlimited to N,N′-dibenzylethylenediamine, chloroprocaine, choline,ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and inorganic salts, such as but not limited to, sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates, mesylates, and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidicgroups, including, but not limited to, carboxylic acids, phosphoricacids, phosphinic acids, sulfonic acids, sulfinic acids and boronicacids. Pharmaceutically acceptable enol ethers include, but are notlimited to, derivatives of formula C═C(OR) where R is alkyl, alkenyl,alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enolesters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyland cycloalkyl. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent orwater molecules.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating cancer,inflammation or rasopathies.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, and unless otherwise indicated, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease or disorder in a subject who has already suffered fromthe disease or disorder, and/or lengthening the time that a subject whohas suffered from the disease or disorder remains in remission. Theterms encompass modulating the threshold, development and/or duration ofthe disease or disorder, or changing the way that a subject responds tothe disease or disorder.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse in an assay that measures such response.

As used herein, the K_(d) refers to the measured equilibriumdissociation constant between a compound (or ligand) and a protein (orbinding domain of a protein).

As used herein, “Ras superfamily” means the protein superfamily of smallguanosine triphosphatases (GTPases) which consists of the five mainfamilies Ras, Rho, Rab, Ran and Arf, or mutants thereof. Subfamilies ofthe five main families are also included, e.g., the Rac subfamily of theRho main family.

As used herein, “Ras” or “Ras family” or “Ras subfamily” or “Ras group”means DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1;NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1;RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG;RERGL; RRAD; RRAS; RRAS2, or mutants thereof.

As used herein, “Rho” or “Rho family” or “Rho subfamily” or “Rho group”means RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG;RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42,or mutants thereof.

As used herein, “Rac” or “Rac family” or “Rac subfamily” or “Rac group”means RAC1; RAC2; RAC3; RHOG, or mutants thereof.

As used herein, “GTP binding site” or “GTP binding domain” both mean theregion of a protein which binds GTP, and the surrounding region of saidprotein in which another compound may bind, wherein such binding blocksthe ability of GTP to bind to said protein.

As used herein, “GDP binding site” or “GDP binding domain” both mean theregion of a protein which binds GDP, and the surrounding region of saidprotein in which another compound may bind, wherein such binding blocksthe ability of GDP to bind to said protein.

As used herein, “guanosine binding region” means a region of a proteinwhich is part of the GDP binding domain or GTP binding domain, thatmediates interaction with the guanosine portion of GDP or GTP.

As used herein, “metal region” means a region of a protein which is partof the GDP binding domain or GTP binding domain, that is proximal to amagnesium (Mg202) binding site.

As used herein, “alternative Tyr32 conformation” means the conformationof the GTP or GDP binding domain in the region of Tyr 32 in KRas crystalstructure PDB code:3gft in comparsion to the KRas crystal structure PDBcode:4epr.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter enzymatic and biological activities of the substance.Methods for purification of the compounds to produce substantiallychemically pure compounds are known to those of skill in the art. Asubstantially chemically pure compound may, however, be a mixture ofstereoisomers. In such instances, further purification might increasethe specific activity of the compound. The instant disclosure is meantto include all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (+) and (−), (R)— and (S)—, or(D)- and (L)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, such as chiralreverse phase HPLC. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included. For example, Formula VI includes, but is notlimited to, the three tautomeric structures below when R⁵═H.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is usedas is generally understood by those of skill in this art.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, or 1 to 16 carbons, and arestraight or branched. Alkenyl carbon chains of from 2 to 20 carbons, incertain embodiments, contain 1 to 8 double bonds, and the alkenyl carbonchains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 doublebonds. Alkynyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.Exemplary alkyl, alkenyl and alkynyl groups herein include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl,ethenyl, propenyl, butenyl, pentenyl, acetylenyl and hexynyl. As usedherein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbonchains having from about 1 or about 2 carbons up to about 6 carbons. Asused herein, “alk(en)(yn)yl” refers to an alkyl group containing atleast one double bond and at least one triple bond.

As used herein, “heteroalkyl” refers to a straight or branched aliphatichydrocarbon group having, inserted in the hydrocarbon chain one or moreoxygen, sulfur, including S(═O) and S(═O)₂ groups, or substituted orunsubstituted nitrogen atoms, including —NR— and —N⁺RR— groups, wherethe nitrogen substituent(s) is(are) alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, S(═O)₂R′ or COR′, where R′ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, OY or —NYY′, where Y and Y′ are eachindependently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl orheterocyclyl, in one embodiment having from 1 to about 20 atoms, inanother embodiment having from 1 to 12 atoms in the chain.

As used herein, “cycloalkyl” refers to a saturated mono- or multicyclicring system, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl referto mono- or multicyclic ring systems that respectively include at leastone double bond and at least one triple bond. Cycloalkenyl andcycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbonatoms, with cycloalkenyl groups, in further embodiments, containing 4 to7 carbon atoms and cycloalkynyl groups, in further embodiments,containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl,cycloalkenyl and cycloalkynyl groups may be composed of one ring or twoor more rings which may be joined together in a fused, bridged orspiro-connected fashion. “Cycloalk(en)(yn)yl” refers to a cycloalkylgroup containing at least one double bond and at least one triple bond.In some embodiments, the cycloalkyl ring is unsaturated or partiallysaturated.

As used herein, “carbocyclic” refers to a mono- or multicyclic ringsystem, in which all of the atoms composing the ring are carbon atoms,such as benzene or cyclopropane. In some embodiments, the carbocyclicring is unsaturated or partially saturated.

As used herein, “substituted alkyl,” “substituted alkenyl,” “substitutedalkynyl,” “substituted cycloalkyl,” “substituted cycloalkenyl,” and“substituted cycloalkynyl” refer to alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and cycloalkynyl groups, respectively, that are substitutedwith one or more substituents, in certain embodiments one to three orfour substituents, where the substituents are as defined herein, in oneembodiment selected from Q.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 6 to 19 carbon atoms. Aryl groups include, butare not limited to groups such as fluorenyl, substituted fluorenyl,phenyl, substituted phenyl, naphthyl and substituted naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl andisoquinolinyl.

As used herein, “heterocycloalkyl,” “heterocyclyl” or “heterocyclic”refers to a monocyclic or multicyclic non-aromatic ring system, in oneembodiment of 3 to 10 members, in another embodiment of 4 to 7 members,in a further embodiment of 5 to 6 members, where one or more, in certainembodiments, 1 to 3, of the atoms in the ring system is a heteroatom,that is, an element other than carbon, including but not limited to,nitrogen, oxygen or sulfur. In embodiments where the heteroatom(s)is(are) nitrogen, the nitrogen is optionally substituted with alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino,amidino, sulfonyl or the nitrogen may be quaternized to form an ammoniumgroup where the substituents are selected as above. In some embodiments,the heterocyclyl ring is saturated. In some embodiments, theheterocyclyl ring is unsaturated or partially saturated.

As used herein, “substituted aryl,” “substituted heteroaryl” and“substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclylgroups, respectively, that are substituted with one or moresubstituents, in certain embodiments one to three or four substituents,where the substituents are as defined herein, in one embodiment selectedfrom Q.

As used herein, “aralkyl” or “arylalkyl” refers to an alkyl group inwhich one of the hydrogen atoms of the alkyl is replaced by an arylgroup.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups thatbehave substantially similar to halides. Such compounds can be used inthe same manner and treated in the same manner as halides. Pseudohalidesinclude, but are not limited to, cyano, thiocyanate, selenocyanate,trifluoromethoxy, and azide.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl, trifluoromethyl and1-chloro-2-fluoroethyl.

As used herein, “haloalkoxy” refers to RO in which R is a haloalkylgroup.

As used herein, “carboxy” refers to a divalent radical, —C(O)O—.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R isalkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl”refers to —C(O)NR′R in which R′ and R are independently alkyl, includinglower alkyl; “carboxamide” refers to groups of formula —NR′COR in whichR′ and R are independently alkyl, including lower alkyl.

As used herein, “arylalkylaminocarbonyl” refers to —C(O)NRR′ in whichone of R and R′ is aryl, including lower aryl, such as phenyl, and theother of R and R′ is alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which R isaryl, including lower aryl, such as phenyl.

As used herein, “hydroxycarbonyl” refers to —COOH.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,including lower alkyl.

As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R is aryl,including lower aryl, such as phenyl.

As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, in whichR is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, in whichR is aryl, including lower aryl, such as phenyl.

Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there may be one or more substituents present. Forexample, “haloalkyl” may include one or more of the same or differenthalogens.

As used herein, “cyclic structure” may be a cycloalkyl, carbocyclic,heterocyclic, aryl or heteroaryl group.

Where substitution is not specified (e.g., “aryl”), there may be one ormore substituents present. For example, “aryl” may include a“substituted aryl” group. In some embodiments, each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents, in one embodiment one, two, three or four substituents Q,where each Q is independently selected from (a) deuterium, cyano, halo,and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of whichis further optionally substituted with one or more, in one embodiment,one, two, three, or four, substituents Q^(a); and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR′, —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heterocyclyl. In some embodiments, two Qsubstituents together with the atoms to which they are attached, mayform a fused ring system.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, the IUPAC-IUB Commissionon Biochemical Nomenclature (see, (1972) Biochem. 11:942-944), or theIUPAC Nomenclature of Organic Chemistry (see, Favre H A and Powell W H,Nomenclature of Organic Chemistry: IUPAC Recommendations and PreferredNames 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: PrintISBN 978-0-85404-182-4, PDF eISBN 978-1-84973-306-9, DOI10.1039/9781849733069; Nomenclature of Organic Chemistry, Sections A, B,C, D, E, F, and H, Pergamon Press, Oxford, 1979. Copyright 1979 IUPAC;and A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations1993), 1993, Blackwell Scientific publications, Copyright 1993 IUPAC).

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician. A therapeutically effectiveamount of a compound provided herein can be administered in one dose(i.e., a single dose administration) or divided and administered overtime (i.e., continuous administration or multiple sub-doseadministration). Single dose administration, continuous administration,or multiple sub-dose administration can be repeated, for example, tomaintain the level of the compound in a biological molecule (e.g., aprotein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 22nd ed.; Loyd et al., Eds.; ThePharmaceutical Press, 2012; Handbook of Pharmaceutical Excipients, 7thed.; Rowe et al., Eds.; The Pharmaceutical Press, 2012; Handbook ofPharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse InformationResources, Inc., 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC, 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The term “percent by weight” or “% by weight” refers to the weight of aspecified component (e.g., an active compound or excipient) in acomposition (e.g., a pharmaceutical composition) as a percentage of thetotal weight of the composition. Thus, the sum of the weight percentagesof all the components in a composition is 100%.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer or an isotopic variant of acompound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof one enantiomer and about 5% or less of the other enantiomer based onthe total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such compounds. In certain embodiments, an “isotopic variant”of a compound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), tritium(³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), carbon-14(¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O) oxygen-17 (¹⁷O),oxygen-18 (¹⁸O) fluorine-17 (¹⁷F), fluorine-18 (¹⁸F), phosphorus-31(³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S),sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S),chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125 (¹²⁵I),iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). In certainembodiments, an “isotopic variant” of a compound is in a stable form,that is, non-radioactive. In certain embodiments, an “isotopic variant”of a compound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), carbon-12(¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16(¹⁶O) oxygen-17 (¹⁷O), oxygen-18 (¹⁸O) fluorine-17 (¹⁷F), phosphorus-31(³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79 (⁷⁹Br),bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certain embodiments, an“isotopic variant” of a compound is in an unstable form, that is,radioactive. In certain embodiments, an “isotopic variant” of a compoundcontains unnatural proportions of one or more isotopes, including, butnot limited to, tritium (³H), carbon-11 (¹¹C), carbon-14 (¹⁴C),nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18 (¹⁸F),phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S), chlorine-36(³⁶Cl), iodine-123 (123I), iodine-125 (¹²⁵I), iodine-129 (¹²⁹I), andiodine-131 (¹³¹I). It will be understood that, in a compound as providedherein, any hydrogen can be ²H, for example, or any carbon can be ¹³C,as example, or any nitrogen can be ¹⁵N, as example, and any oxygen canbe ¹⁸O, where feasible according to the judgment of one of skill. Incertain embodiments, an “isotopic variant” of a compound containsunnatural proportions of deuterium. In some embodiments, apharmaceutically acceptable derivative of a compound is an isotopicvariant.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The phrase “an isotopic variant thereof; or a pharmaceuticallyacceptable salt thereof; or a pharmaceutically acceptable solvatethereof” has the same meaning as the phrase “an isotopic variant of thecompound referenced therein; or a pharmaceutically acceptable salt ofthe compound referenced therein; or a pharmaceutically acceptable saltof an isotopic variant of the compound referenced therein; or apharmaceutically acceptable solvate of the compound referenced therein;or a pharmaceutically acceptable solvate of an isotopic variant of thecompound referenced therein; or a pharmaceutically acceptable solvate ofa pharmaceutically acceptable salt of the compound referenced therein;or a pharmaceutically acceptable solvate of a pharmaceuticallyacceptable salt of an isotopic variant of the compound referencedtherein or its variant or its variant.”

5.2. Ras GTP Binding Domain

Data Concerning the Affinity of GTP to the Ras GTP Binding Domain

For the first time, the affinity of GTP for the GTP binding domain ofK-Ras utilizing a Scintillation Proximity Assay (SPA) and MicroScaleThermophoresis (MST) has been measured and disclosed herein. Thesemethods were not available when Wittinghofer and colleagues undertooktheir studies.

In SPA and MST studies, it was found and is disclosed herein that theaffinity of GTP for the K-Ras GTP binding domain across wild type andmutant K-Ras is in the range of 100-465 nanomolar (see results in Table2). This therefore led to the novel, unanticipated conclusion thatcompounds such as small molecules could be discovered that would bind toa Ras GTP binding domain and compete with the binding of GTP to Ras. SPAand MST studies performed on the Rac-1 and Rho-A members of the Rhosubfamily show that the affinity of GTP for the binding domain of theseRho subfamily members is in the range of 120-170 nanomolar (see resultsin Table 2).

TABLE 2 MST and SPA Results for GTP Affinity for K-Ras and Rho SubfamilyBinding Domains Protein MST SPA K-Ras (wild type) 463 ± 2 nM  243 ± 15nM K-Ras (G12D) 244 ± 12 nM 270 ± 15 nM K-Ras (G12C) 207 ± 46 nM 258 ±18 nM K-Ras (Q61H) 157 ± 21 nM 118 ± 11 nM K-Ras (Q61H/G12D)  268 ± 108nM 135 ± 19 nM K-Ras (Q61H/G12C) 266 ± 57 nM 104 ± 11 nM Rac-1 166 ± 10nM 151 ± 14 nM Rho-A 130 ± 5 nM  129 ± 12 nM

See Khawaja et al., “Scintillation proximity assay in lead discovery”,Expert Opin. Drug Discov., 2008 November; 3(11):1267-80 regarding SPAprocedures. See the following references regarding MST technology:Wienken et al., Nature Communications (2010), Protein binding assays inbiological liquids using MicroScale Thermophoresis; Jerabek-Willemsen etal., ASSAY and Drug Development Technologies (2011), Molecularinteraction studies using MicroScale Thermophoresis; Lin et al., Cell(2012), Inhibition of basal FGF receptor signaling by dimeric Grb2;Seidel et al., Angewandte Chemie (2012), Label-Free MicroScaleThermophoresis discriminates sites and affinity of protein-ligandbinding; Seidel et al., Methods (2012), MicroScale Thermophoresisquantifies biomolecular interactions under previously challengingconditions; Parker & Newstead, Nature (2014), Molecular basis of nitrateuptake by the plant nitrate transporter NRT1.1; and Jerabek-Willemsen etal., Journal of Molecular Structure (2014), MicroScale Thermophoresis:Interaction analysis and beyond.

The discovery of Small Molecules that Bind to a Ras GTP Binding Domainin Competition with GTP

Provided herein is an assay for the identification of small moleculesthat bind to a Ras GTP binding domain in competition with GTP.

The useful and novel approach for drug discovery described herein is toidentify small molecule inhibitors that will compete and blockinteractions between GTP and GTP-binding proteins. By interacting withthe GDP/GTP-binding site of GTP-binding proteins small molecules soidentified may induce a GDP-bound or other inactive conformation of theGTP-binding proteins and thus block signal transduction pathwaysdownstream of the GTP-binding protein.

The assay developed measures and quantifies the ability of tested smallmolecules in a cell-free system to compete with GTP or GDP binding. Theassay can be used in low volumes or for High Throughput Screening (HTS)to screen a compound library and to support medicinal chemistryStructure Activity Relationship (SAR) efforts.

This is a competitive binding assay. It involves the immobilization of aprotein on solid phase, interaction with a small molecule drugcandidate, and then competitive binding with a labeled native GTP or GDPligand.

In one embodiment, provided herein is a method of testing the ability ofone or more compounds to bind to the GTP binding domain and to competefor GTP binding of one or more members of the Ras superfamilycomprising:

a) expressing a Ras superfamily protein or mutant thereof as a taggedprotein;

b) contacting the one or more compounds to the tagged protein, followedby incubating the combination;

c) adding labeled-GTP or labeled-GDP to each protein-compoundcombination, followed by incubating the resulting mixture; and

d) measuring the amount of bound labeled-GTP or bound labeled-GDP.

In one embodiment, the method further comprises between step a) and stepb): adding the tagged protein to one or more wells of a ligand coatedsingle or multi-well plate and incubating the tagged protein.

In one embodiment of the method, one or more members of the Rassuperfamily is Ras. In one embodiment of the method, the Ras is DIRAS1;DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS 1; NKIRAS2; NRAS;RALA; RALB; RAP 1A; RAP 1B; RAP2A; RAP2B; RAP2C; RASD 1; RASD2; RASL10A; RASL 10B; RASL 11A; RASL 11B; RASL12; REM1; REM2; RERG; RERGL;RRAD; RRAS; or RRAS2. In one embodiment of the method, the Ras is HRAS,KRAS, NRAS, or a mutant thereof. In one embodiment of the method, theRas is HRAS or a mutant thereof. In one embodiment of the method, theRas is KRAS or a mutant thereof. In one embodiment of the method, theRas is NRAS or a mutant thereof.

In one embodiment of the method, the Ras superfamily protein is KRasG12D mutant protein. In one embodiment of the method, the Rassuperfamily protein is KRas G12C mutant protein. In one embodiment ofthe method, the Ras superfamily protein is KRas wild type protein. Inone embodiment of the method, the Ras superfamily protein is KRas Q61Hmutant protein. In one embodiment of the method, the Ras superfamilyprotein is KRas G12D/Q61H double mutant protein. In one embodiment ofthe method, the Ras superfamily protein is G12C/Q61H double mutant.

In one embodiment of the method, one or more members of the Rassuperfamily is Rho. In one embodiment of the method, the Rho is RHOA;RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ;RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or a mutantthereof. In one embodiment of the method, the Ras superfamily protein isRho-A protein.

In one embodiment of the method, one or more members of the Rassuperfamily is Rac. In one embodiment of the method, the Rho is Rac or amutant thereof. In one embodiment of the method, the Rac is RAC1; RAC2;RAC3; RHOG, or a mutant thereof. In one embodiment of the method, theRas superfamily protein is Rac-1 protein.

In one embodiment of the method, the tagged protein is tagged with His.In one embodiment of the method, the ligand is nickel. In one embodimentof the method, the labeled-GTP is Cy3-GTP or Cy5-GTP. In one embodimentof the method, the buffer is Buffer-I which comprises 50 mM Tris (pH7.5), 150 mM NaCl, 1 mM MgCl₂, and 1 mM DTT. In another embodiment ofthe method, the buffer is Buffer-I which comprises 50 mM Tris (pH 7.5),1 mM MgCl₂, and 1 mM DTT.

The form of the assay involves the binding of His-tagged protein tonickel coated plates and a native form of GTP covalently labeled withCy3 or Cy5 fluorescent probes.

In theory, the assay is suitable for use with any GTP or GDP bindingprotein. The Examples demonstrate that the assay can be utilized for Rasand Ras mutants, Rac-1 and Rho-A human proteins expressed and purifiedas recombinant proteins.

Different tag/ligand combinations can be used in the assay. The proteinmay be expressed as a fusion protein with a tag such as His, HA, Flag orGST; or, the protein can be labeled by a tag such as biotin via chemicalreaction. The counter molecule (ligand or binder) interacting with thetag will bind or coat the solid phase. The solid phase could be a plate(96, 384 or 1536 wells plate) and column beads such as sepharose,agarose and cellulose. Binders could include nickel, antibodies,glutathione and streptavidin. Examples of tag:ligand combinationsinclude His (polyhistidine, at least 6 histidines):nickel, GST(Glutathione-S-transferase):glutathione, HA (amino acids 98-106 of humaninfluenza hemagglutinin):anti-HA antibodies, Fc (constant region ofhuman IgG):protein A, FLAG (the peptide DYDDDDK):Antibodies (M1. M2,4E11), Myc (the peptide EQKLISEED derived the myc protein): Anti-mycantibodies, and biotin: streptavidin (or avidin).

Heretofore, attempts to measure small molecule competitors for GTPprotein interactions have relied on the ability of the tested smallmolecules to prevent binding of labeled GTP to the GTP-binding protein.A novel component of this assay is the use of the highly sensitive Cy3or Cy5 probes. Similar probes which might be used include other highsensitivity fluorophores that can be detected at concentrations below 1micromolar in solution, and radioactive labeling. The inventors are notaware of any publication suggesting the adaptation of the probes we haveused, or similar probes, for use in a competitive binding assay.

The Identification of Amino Acids in the Ras GTP Binding Domain Enablingthe Development and Function of Small Molecule Targeted Therapeutics

As noted above, it has also been discovered that amino acids in the RasGTP binding domain, including Ala11, Gly12, Val 14, Gly15, Lys 16,Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 andMg202, enable the heretofore unanticipated competitive binding to thatdomain between compounds, such as small molecules, and GTP. It has alsobeen discovered that amino acids in the Ras GTP binding domain,including Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 and Mg202, enable theheretofore unanticipated competitive binding to that domain betweencompounds, such as small molecules, and GTP.

As described in Example 1, molecular modeling studies incorporating Rassuperfamily protein structures from the RCSB PDB (www.rcsb.org) witheither GDP, the GTP analog GNP (guanosine 5′-[β,γ-imido]triphosphatetrisodium salt hydrate), or small molecules disclosed herein, were usedto determine the amino acids in the Ras superfamily domain in closeproximity to the GDP, GTP or small molecules when bound to the Rassuperfamily protein.

As noted above, it has also been discovered that amino acids in the Rac1GTP binding domain, including Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, and Mg202, enable the heretofore unanticipatedcompetitive binding to that domain between compounds, such as smallmolecules, and GTP.

As noted above, it has also been discovered that amino acids in the RhoAGTP binding domain, including Gly14, Ala15, Cys16, Gly17, Lys18, Thr19,Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118,Asp120, Lys162, and Mg202, enable the heretofore unanticipatedcompetitive binding to that domain between compounds, such as smallmolecules, and GTP.

5.3. Methods of Treatment

5.3.1 Cancer

In one embodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound thatinhibits the function of one or more members of the Ras superfamily bybinding to the GTP binding domain or one or more members of the Rassuperfamily. In one embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that inhibits the function of Ras by binding to a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 10 μM and a K_(d) of less than 10 μM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Ras GTP binding domain with an IC₅₀ of less than 1 μM and a K_(d)of less than 1 μM. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 500 nM and a K_(d) of less than 500 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Ras GTP binding domain with an IC₅₀ of less than 470 nM and a K_(d)of less than 470 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 270 nM and a K_(d) of less than 270 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Ras GTP binding domain with an IC₅₀ of less than 200 nM and a K_(d)of less than 200 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 150 nM and a K_(d) of less than 150 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Ras GTP binding domain with an IC₅₀ of less than 100 nM and a K_(d)of less than 100 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with greaterthan 25% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing cancer, which comprises administeringto a subject a compound that binds to a Ras GTP binding domain withgreater than 50% inhibition at 20 μM. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with greater than 80% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Ras GTP binding domain with greater than 85% inhibition at 20 μM.In another embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to a Ras GTP binding domain with greater than 90% inhibitionat 20 μM. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with greater than 95%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with greaterthan 99% inhibition at 20 μM. In one embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that inhibits the function of Rho by binding toa Rho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to a Rho GTP binding domain with anIC₅₀ of less than 10 μM and a K_(d) of less than 10 μM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rho GTP binding domain with an IC₅₀ of less than 1 μM and a K_(d)of less than 1 μM. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 500 nM and a K_(d) of less than 500 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rho GTP binding domain with an IC₅₀ of less than 270 nM and a K_(d)of less than 270 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 200 nM and a K_(d) of less than 200 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rho GTP binding domain with an IC₅₀ of less than 150 nM and a K_(d)of less than 150 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 130 nM and a K_(d) of less than 130 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rho GTP binding domain with an IC₅₀ of less than 100 nM and a K_(d)of less than 100 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with greaterthan 25% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing cancer, which comprises administeringto a subject a compound that binds to a Rho GTP binding domain withgreater than 50% inhibition at 20 μM. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with greater than 80% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rho GTP binding domain with greater than 85% inhibition at 20 μM.In another embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to a Rho GTP binding domain with greater than 90% inhibitionat 20 μM. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with greater than 95%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with greaterthan 99% inhibition at 20 μM. In one embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that inhibits the function of Rac by binding toa Rac GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to a Rac GTP binding domain with anIC₅₀ of less than 10 μM and a K_(d) of less than 10 μM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rac GTP binding domain with an IC₅₀ of less than 1 μM and a K_(d)of less than 1 μM. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with an IC₅₀of less than 500 nM and a K_(d) of less than 500 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rac GTP binding domain with an IC₅₀ of less than 270 nM and a K_(d)of less than 270 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with an IC₅₀of less than 200 nM and a K_(d) of less than 200 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rac GTP binding domain with an IC₅₀ of less than 170 nM and a K_(d)of less than 170 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with an IC₅₀of less than 150 nM and a K_(d) of less than 150 nM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rac GTP binding domain with an IC₅₀ of less than 100 nM and a K_(d)of less than 100 nM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with greaterthan 25% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing cancer, which comprises administeringto a subject a compound that binds to a Rac GTP binding domain withgreater than 50% inhibition at 20 μM. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to a Rac GTPbinding domain with greater than 80% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto a Rac GTP binding domain with greater than 85% inhibition at 20 μM.In another embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to a Rac GTP binding domain with greater than 90% inhibitionat 20 μM. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with greater than 95%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with greaterthan 99% inhibition at 20 μM.

In another embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to one or more of Ala 11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to two or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to three ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to four or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to five or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to seven or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to eight ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to nine or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to ten or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to eleven or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to twelve or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to fourteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto fifteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to sixteen or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to seventeenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to eighteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto nineteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to twenty or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to twenty-oneor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to twenty-two or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto twenty-three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to all of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain.

In another embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to two or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to four or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to six or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to eight or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to ten or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto eleven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to twelve or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to fourteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto fifteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to sixteen or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto seventeen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to eighteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto nineteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing cancer, which comprises administering to asubject a compound that binds to twenty or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto twenty-one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to twenty-two or more of Ala11,Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31,Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto twenty-three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to all of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain.

In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS;KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12;REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment,the Ras is HRAS, KRAS or NRAS. In one embodiment, the Ras is HRAS. Inone embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. Inanother embodiment, the Ras is a mutant form of a Ras described herein.

In another embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19,Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118,Asp120, Lys162 or Mg202 in a Rho GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto two or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20,Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120,Lys162 or Mg202 in a Rho GTP binding domain. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to three ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to four or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to five or more of Gly14, Ala15,Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35,Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to six or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to seven or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to eight or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19,Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118,Asp120, Lys162 or Mg202 in a Rho GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto nine or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20,Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120,Lys162 or Mg202 in a Rho GTP binding domain. In another embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to ten ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing cancer, which comprisesadministering to a subject a compound that binds to eleven or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing cancer, which comprises administeringto a subject a compound that binds to twelve or more of Gly14, Ala15,Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35,Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to thirteen or more of Gly14, Ala15,Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35,Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to fourteen or more of Gly14, Ala15,Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35,Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to fifteen or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing cancer, which comprises administering to a subject acompound that binds to sixteen or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to seventeen or more of Gly14, Ala15, Cys16, Gly17, Lys18,Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59,Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsall of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain.

In one embodiment, the Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3;RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3;RAC1; RAC2; RAC3 or CDC42. In one embodiment, the Rho is RHOA. Inanother embodiment, the Rho is a mutant form of a Rho described herein.

In one embodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19,Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119,Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In one embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to two ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a highly conserved Rho GTP binding domain. In one embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to three ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a Rac GTP binding domain. In one embodiment, provided herein isa method of treating or preventing cancer, which comprises administeringto a subject a compound that binds to four or more of Gly12, Ala13,Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59,Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTPbinding domain. In one embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to five or more of Gly12, Ala13, Gly15,Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115,Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP bindingdomain. In one embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to six or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto seven or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19,Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119,Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In one embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to eight ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a Rac GTP binding domain. In one embodiment, provided herein isa method of treating or preventing cancer, which comprises administeringto a subject a compound that binds to nine or more of Gly12, Ala13,Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59,Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTPbinding domain. In one embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to ten or more of Gly12, Ala13, Gly15,Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115,Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP bindingdomain. In one embodiment, provided herein is a method of treating orpreventing cancer, which comprises administering to a subject a compoundthat binds to eleven or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound that bindsto twelve or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19,Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119,Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In one embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to thirteenor more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28,Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157,Ala159, or Mg202 in a Rac GTP binding domain. In one embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to fourteenor more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28,Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157,Ala159, or Mg202 in a Rac GTP binding domain. In one embodiment,provided herein is a method of treating or preventing cancer, whichcomprises administering to a subject a compound that binds to fifteen ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a Rac GTP binding domain. In one embodiment, provided herein isa method of treating or preventing cancer, which comprises administeringto a subject a compound that binds to sixteen or more of Gly12, Ala13,Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59,Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTPbinding domain. In one embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to seventeen or more of Gly12, Ala13,Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59,Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTPbinding domain. In one embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to eighteen or more of Gly12, Ala13,Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59,Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTPbinding domain. In one embodiment, provided herein is a method oftreating or preventing cancer, which comprises administering to asubject a compound that binds to all of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain.

In one embodiment, the Rho is Rac. In one embodiment the Rac is RAC1;RAC2; RAC3 or RHOG. In one embodiment, the Rac is RAC1. In anotherembodiment, the Rac is a mutant form of a Rac described herein.

In one embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to one or more members of the Rassuperfamily. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Ras. In oneembodiment, the compounds provided herein inhibit GTP binding to Rho. Inone embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Rac. In one embodiment, thecompound for use in the methods and compositions provided herein inhibitGTP binding to Ras and Rho. In one embodiment, the compound for use inthe methods and compositions provided herein inhibit GTP binding to Rasand Rac. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Rho and Rac. In oneembodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Ras, Rho and Rac. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 2000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1500 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1250 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 665 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 500 daltons. In anotherembodiment, the compound for use in the methods and compositionsprovided herein contains an oxadiazole, thiadiazole or triazole moiety.In another embodiment, the compound for use in the methods andcompositions provided herein contains a 1,2,4-oxadiazole,1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole,2-(pyridine-2-yl)pyrimidine-4-amine, 2-(pyridine-2-yl)pyrimidine-4-ol,2-(pyridine-2-yl)pyrimidine-4-(1H)-one,2-(pyridin-2-yl)pyrimidin-4(3H)-one,2-(pyridin-2-yl)pyrimidin-4(1H)-imine or2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, thecompound for use in the methods and compositions provided hereincontains a 2-(pyridin-2-yl)pyrimidine-4-amine,2-(pyridin-2-yl)pyrimidine-4-ol, 2-(pyridin-2-yl)pyrimidine-4-(1H)-one,2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one,2-(imidazol-2-yl)pyrimidin-4(1H)-one,2-(imidazol-2-yl)pyrimidin-4-amine,2-(imidazol-2-yl)pyrimidin-4(3H)-imine,2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol,2-(imidazol-4-yl)pyrimidin-4(3H)-one,2-(imidazol-4-yl)pyrimidin-4(1H)-one,2-(imidazol-4-yl)pyrimidin-4-amine,2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

In one embodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a subject a compound providedherein, or a derivative thereof.

In another embodiment, provided herein is method of managing cancer,which comprises administering to a subject a compound provided herein,or a derivative thereof.

Also provided herein are methods of treating subjects who have beenpreviously treated for cancer but are non-responsive to standardtherapies, as well as those who have not previously been treated. Alsoprovided are methods of treating subjects regardless of subject's age,although some diseases or disorders are more common in certain agegroups. Also provided are methods of treating subjects who haveundergone surgery in an attempt to treat the disease or condition atissue, as well as those who have not. Because subjects with cancer haveheterogeneous clinical manifestations and varying clinical outcomes, thetreatment given to a subject may vary, depending on his/her prognosis.The skilled clinician will be able to readily determine without undueexperimentation specific secondary agents, types of surgery, and typesof non-drug based standard therapy that can be effectively used to treatan individual subject with cancer.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood borne tumors. The term “cancer” refers to disease ofskin tissues, organs, blood, and vessels, including, but not limited to,cancers of the bladder, bone, blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis,throat, and uterus. Specific cancers include, but are not limited to,advanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastase, glioblastoma multiforms,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant giolma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma,karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuselarge B-Cell lymphoma, low grade follicular lymphoma, malignantmelanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma.

In certain embodiments, the cancer is a solid tumor. In certainembodiments, the solid tumor is metastatic. In certain embodiments, thesolid tumor is drug-resistant. In certain embodiments, the solid tumoris hepatocellular carcinoma, prostate cancer, pancreatic cancer, lungcancer, ovarian cancer, colon cancer, small intestine cancer, biliarytract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer,urinary tract cancer, or glioblastoma.

In certain embodiments, the cancer is a blood borne tumor. In certainembodiments, the blood borne tumor is metastatic. In certainembodiments, the blood borne tumor is drug resistant. In certainembodiments, the cancer is leukemia.

In one embodiment, methods provided herein encompass treating,preventing or managing various types of leukemias such as chroniclymphocytic leukemia (CLL), chronic myelocytic leukemia (CIVIL), acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acutemyeloblastic leukemia (AML) by administering a therapeutically effectiveamount of a compound provided herein or a derivative thereof.

In some embodiments, the methods provided herein encompass treating,preventing or managing acute leukemia in a subject. In some embodiments,the acute leukemia is acute myeloid leukemia (AML), which includes, butis not limited to, undifferentiated AML (M0), myeloblastic leukemia(M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3variant (M3V)), myelomonocytic leukemia (M4 or M4 variant witheosinophilia (M4E)), monocytic leukemia (M5), erythroleukemia (M6), andmegakaryoblastic leukemia (M7). In one embodiment, the acute myeloidleukemia is undifferentiated AML (M0). In one embodiment, the acutemyeloid leukemia is myeloblastic leukemia (M1). In one embodiment, theacute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment,the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant(M3V)). In one embodiment, the acute myeloid leukemia is myelomonocyticleukemia (M4 or M4 variant with eosinophilia (M4E)). In one embodiment,the acute myeloid leukemia is monocytic leukemia (M5). In oneembodiment, the acute myeloid leukemia is erythroleukemia (M6). In oneembodiment, the acute myeloid leukemia is megakaryoblastic leukemia(M7). Thus, the methods of treating, preventing or managing acutemyeloid leukemia in a subject comprise the step of administering to thesubject an amount of a compound provided herein or a derivative thereofeffective to treat, prevent or manage acute myeloid leukemia alone or incombination. In some embodiments, the methods comprise the step ofadministering to the subject a compound provided herein or a derivativethereof in combination with a second active agent in amounts effectiveto treat, prevent or manage acute myeloid leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing acute lymphocytic leukemia (ALL) in a subject. Insome embodiments, acute lymphocytic leukemia includes leukemia thatoriginates in the blast cells of the bone marrow (B-cells), thymus(T-cells), and lymph nodes. The acute lymphocytic leukemia can becategorized according to the French-American-British (FAB) MorphologicalClassification Scheme as L1-Mature-appearing lymphoblasts (T cells orpre-B-cells), L2-Immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells), and L3-Lymphoblasts (B-cells;Burkitt's cells). In one embodiment, the acute lymphocytic leukemiaoriginates in the blast cells of the bone marrow (B-cells). In oneembodiment, the acute lymphocytic leukemia originates in the thymus(T-cells). In one embodiment, the acute lymphocytic leukemia originatesin the lymph nodes. In one embodiment, the acute lymphocytic leukemia isL1 type characterized by mature-appearing lymphoblasts (T-cells orpre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2type characterized by immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acutelymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells;Burkitt's cells). In certain embodiments, the acute lymphocytic leukemiais T cell leukemia. In one embodiment, the T-cell leukemia is peripheralT-cell leukemia. In another embodiment, the T-cell leukemia is T-celllymphoblastic leukemia. In another embodiment, the T-cell leukemia iscutaneous T-cell leukemia. In another embodiment, the T-cell leukemia isadult T-cell leukemia. Thus, the methods of treating, preventing ormanaging acute lymphocytic leukemia in a subject comprise the step ofadministering to the subject an amount of a compound provided herein ora derivative thereof effective to treat, prevent or manage acutelymphocytic leukemia alone or in combination with a second active agent.In some embodiments, the methods comprise the step of administering tothe subject a compound provided herein or a derivative thereof incombination with a second active agent in amounts effective to treat,prevent or manage acute lymphocytic leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing chronic myelogenous leukemia (CIVIL) in asubject. The methods comprise the step of administering to the subjectan amount of a compound provided herein or a derivative thereofeffective to treat, prevent or manage chronic myelogenous leukemia. Insome embodiments, the methods comprise the step of administering to thesubject a compound provided herein or a derivative thereof incombination with a second active agent in amounts effective to treat,prevent or manage chronic myelogenous leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing chronic lymphocytic leukemia (CLL) in a subject.The methods comprise the step of administering to the subject an amountof a compound provided herein or a derivative thereof effective totreat, prevent or manage chronic lymphocytic leukemia. In someembodiments, the methods comprise the step of administering to thesubject a compound provided herein or a derivative thereof incombination with a second active agent in amounts effective to treat,prevent or manage chronic lymphocytic leukemia.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing disease in subjects with impaired renalfunction. In certain embodiments, provided herein are method oftreating, preventing, and/or managing cancer in subjects with impairedrenal function. In certain embodiments, provided herein are methods ofproviding appropriate dose adjustments for subjects with impaired renalfunction due to, but not limited to, disease, aging, or other subjectfactors.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing lymphoma, including non-Hodgkin's lymphoma.In some embodiments, provided herein are methods for the treatment ormanagement of non-Hodgkin's lymphoma (NHL), including but not limitedto, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing multiple myeloma, includingrelapsed/refractory multiple myeloma in subjects with impaired renalfunction or a symptom thereof, comprising administering atherapeutically effective amount of a compound provided herein, or aderivative thereof to a subject having relapsed/refractory multiplemyeloma with impaired renal function.

In certain embodiments, a therapeutically or prophylactically effectiveamount of the compound is from about 0.005 to about 1,000 mg per day,from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mgper day, from about 0.01 to about 100 mg per day, from about 0.1 toabout 100 mg per day, from about 0.5 to about 100 mg per day, from about1 to about 100 mg per day, from about 0.01 to about 50 mg per day, fromabout 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day,from about 1 to about 50 mg per day, from about 0.02 to about 25 mg perday, from about 0.05 to about 10 mg per day, from about 0.05 to about 5mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 toabout 5 mg per day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is about 0.1, about 0.2, about 0.5, about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 15, about 20, about 25, about 30, about 40, about 45, about 50,about 60, about 70, about 80, about 90, about 100, or about 150 mg perday.

In one embodiment, the recommended daily dose range of the compoundprovided herein, or a derivative thereof, for the conditions describedherein lie within the range of from about 0.5 mg to about 50 mg per day,in one embodiment given as a single once-a-day dose, or in divided dosesthroughout a day. In some embodiments, the dosage ranges from about 1 mgto about 50 mg per day. In other embodiments, the dosage ranges fromabout 0.5 to about 5 mg per day. Specific doses per day include 0.1,0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

In a specific embodiment, the recommended starting dosage may be 0.5, 1,2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, therecommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. Thedose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In aspecific embodiment, the compound can be administered in an amount ofabout 25 mg/day. In a particular embodiment, the compound can beadministered in an amount of about 10 mg/day. In a particularembodiment, the compound can be administered in an amount of about 5mg/day. In a particular embodiment, the compound can be administered inan amount of about 4 mg/day. In a particular embodiment, the compoundcan be administered in an amount of about 3 mg/day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is from about 0.001 to about 100 mg/kg/day, from about0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, fromabout 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day,0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, fromabout 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day,from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 toabout 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.

The administered dose can also be expressed in units other thanmg/kg/day. For example, doses for parenteral administration can beexpressed as mg/m²/day. One of ordinary skill in the art would readilyknow how to convert doses from mg/kg/day to mg/m²/day to given eitherthe height or weight of a subject or both (see,www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1mg/kg/day for a 65 kg human is approximately equal to 38 mg/m²/day.

In certain embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 0.001 to about 500 μM, about 0.002 to about200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, fromabout 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 toabout 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20μM, or from about 1 to about 20 μM.

In other embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 5 to about 100 nM, about 5 to about 50 nM,about 10 to about 100 nM, about 10 to about 50 nM or from about 50 toabout 100 nM.

As used herein, the term “plasma concentration at steady state” is theconcentration reached after a period of administration of a compoundprovided herein, or a derivative thereof. Once steady state is reached,there are minor peaks and troughs on the time dependent curve of theplasma concentration of the compound.

In certain embodiments, the amount of the compound administered issufficient to provide a maximum plasma concentration (peakconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM,from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, fromabout 0.5 to about 20 μM, or from about 1 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide a minimum plasma concentration (troughconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM,from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, fromabout 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide an area under the curve (AUC) of the compound,ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 toabout 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, orfrom about 5,000 to about 10,000 ng*hr/mL.

In certain embodiments, the subject to be treated with one of themethods provided herein has not been treated with anticancer therapyprior to the administration of the compound provided herein, or aderivative thereof. In certain embodiments, the subject to be treatedwith one of the methods provided herein has been treated with anticancertherapy prior to the administration of the compound provided herein, ora derivative thereof. In certain embodiments, the subject to be treatedwith one of the methods provided herein has developed drug resistance tothe anticancer therapy.

The methods provided herein encompass treating a patient regardless ofsubject's age, although some diseases or disorders are more common incertain age groups.

Depending on the disease to be treated and the subject's condition, thecompound provided herein, or a derivative thereof, may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,CIV, intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration. The compoundprovided herein, or a derivative thereof, may be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants and vehicles, appropriate for each routeof administration.

In one embodiment, the compound provided herein, or a derivativethereof, is administered orally. In another embodiment, the compoundprovided herein, or a derivative thereof, is administered parenterally.In yet another embodiment, the compound provided herein, or a derivativethereof, is administered intravenously.

The compound provided herein, or a derivative thereof, can be deliveredas a single dose such as, e.g., a single bolus injection, or oraltablets or pills; or over time, such as, e.g., continuous infusion overtime or divided bolus doses over time. The compound can be administeredrepeatedly if necessary, for example, until the subject experiencesstable disease or regression, or until the subject experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205 216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or Mill scan and other commonly accepted evaluation modalities.

The compound provided herein, or a derivative thereof, can beadministered once daily (QD), or divided into multiple daily doses suchas twice daily (BID), three times daily (TID), and four times daily(QID). In addition, the administration can be continuous (i.e., dailyfor consecutive days or every day), intermittent, e.g., in cycles (i.e.,including days, weeks, or months of rest without drug). As used herein,the term “daily” is intended to mean that a therapeutic compound, suchas the compound provided herein, or a derivative thereof, isadministered once or more than once each day, for example, for a periodof time. The term “continuous” is intended to mean that a therapeuticcompound, such as the compound provided herein or a derivative thereof,is administered daily for an uninterrupted period of at least 10 days to52 weeks. The term “intermittent” or “intermittently” as used herein isintended to mean stopping and starting at either regular or irregularintervals. For example, intermittent administration of the compoundprovided herein or a derivative thereof is administration for one to sixdays per week, administration in cycles (e.g., daily administration fortwo to eight consecutive weeks, then a rest period with noadministration for up to one week), or administration on alternate days.The term “cycling” as used herein is intended to mean that a therapeuticcompound, such as the compound provided herein or a derivative thereof,is administered daily or continuously but with a rest period. In somesuch embodiments, administration is once a day for two to six days, thena rest period with no administration for five to seven days.

In some embodiments, the frequency of administration is in the range ofabout a daily dose to about a monthly dose. In certain embodiments,administration is once a day, twice a day, three times a day, four timesa day, once every other day, twice a week, once every week, once everytwo weeks, once every three weeks, or once every four weeks. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once a day. In another embodiment, the compound providedherein, or a derivative thereof, is administered twice a day. In yetanother embodiment, the compound provided herein, or a derivativethereof, is administered three times a day. In still another embodiment,the compound provided herein, or a derivative thereof, is administeredfour times a day.

In certain embodiments, the compound provided herein, or a derivativethereof, is administered once per day from one day to six months, fromone week to three months, from one week to four weeks, from one week tothree weeks, or from one week to two weeks. In certain embodiments, thecompound provided herein, or a derivative thereof, is administered onceper day for one week, two weeks, three weeks, or four weeks. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once per day for 4 days. In one embodiment, the compoundprovided herein, or a derivative thereof, is administered once per dayfor 5 days. In one embodiment, the compound provided herein, or aderivative thereof, is administered once per day for 6 days. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once per day for one week. In another embodiment, thecompound provided herein, or a derivative thereof, is administered onceper day for two weeks. In yet another embodiment, the compound providedherein, or a derivative thereof, is administered once per day for threeweeks. In still another embodiment, the compound provided herein, or aderivative thereof, is administered once per day for four weeks.

Combination Therapy With A Second Active Agent

The compound provided herein, or a derivative thereof, can also becombined or used in combination with other therapeutic agents useful inthe treatment and/or prevention of cancer described herein.

In one embodiment, provided herein is a method of treating, preventing,or managing cancer, comprising administering to a subject a compoundprovided herein, or a derivative thereof; in combination with one ormore second active agents, and optionally in combination with radiationtherapy, blood transfusions, or surgery. Examples of second activeagents are disclosed herein.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein, a compound provided herein, e.g., the compound providedherein, or a derivative thereof) can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of asecond therapy (e.g., a prophylactic or therapeutic agent) to thesubject. Triple therapy is also contemplated herein.

Administration of the compound provided herein, or a derivative thereofand one or more second active agents to a subject can occursimultaneously or sequentially by the same or different routes ofadministration. The suitability of a particular route of administrationemployed for a particular active agent will depend on the active agentitself (e.g., whether it can be administered orally without decomposingprior to entering the blood stream) and the cancer being treated.

The route of administration of the compound provided herein, or aderivative thereof, is independent of the route of administration of asecond therapy. In one embodiment, the compound provided herein, or aderivative thereof, is administered orally. In another embodiment, thecompound provided herein, or a derivative thereof, is administeredintravenously. Thus, in accordance with these embodiments, the compoundprovided herein, or a derivative thereof, is administered orally orintravenously, and the second therapy can be administered orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form. In one embodiment, the compound provided herein, or aderivative thereof, and a second therapy are administered by the samemode of administration, orally or by IV. In another embodiment, thecompound provided herein, or a derivative thereof, is administered byone mode of administration, e.g., by IV, whereas the second agent (ananticancer agent) is administered by another mode of administration,e.g., orally.

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount of the compound provided herein, or a derivative thereof, andany optional additional active agents concurrently administered to thesubject.

One or more second active ingredients or agents can be used togetherwith the compound provided herein, or a derivative thereof, in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies, particularly, therapeutic antibodies to cancerantigens. Typical large molecule active agents are biological molecules,such as naturally occurring or synthetic or recombinant proteins.Proteins that are particularly useful in the methods and compositionsprovided herein include proteins that stimulate the survival and/orproliferation of hematopoietic precursor cells and immunologicallyactive poietic cells in vitro or in vivo. Other useful proteinsstimulate the division and differentiation of committed erythroidprogenitors in cells in vitro or in vivo. Particular proteins include,but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

In certain embodiments, GM-CSF, G-CSF, SCF or EPO is administeredsubcutaneously during about five days in a four or six week cycle in anamount ranging from about 1 to about 750 mg/m²/day, from about 25 toabout 500 mg/m²/day, from about 50 to about 250 mg/m²/day, or from about50 to about 200 mg/m²/day. In certain embodiments, GM-CSF may beadministered in an amount of from about 60 to about 500 mcg/m²intravenously over 2 hours or from about 5 to about 12 mcg/m²/daysubcutaneously. In certain embodiments, G-CSF may be administeredsubcutaneously in an amount of about 1 mcg/kg/day initially and can beadjusted depending on rise of total granulocyte counts. The maintenancedose of G-CSF may be administered in an amount of about 300 (in smallersubjects) or 480 mcg subcutaneously. In certain embodiments, EPO may beadministered subcutaneously in an amount of 10,000 Unit 3 times perweek.

Particular proteins that can be used in the methods and compositionsinclude, but are not limited to: filgrastim, which is sold in the UnitedStates under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.);sargramostim, which is sold in the United States under the trade nameLeukine® (Immunex, Seattle, Wash.); and recombinant EPO, which is soldin the United States under the trade name Epogen® (Amgen, Thousand Oaks,Calif.).

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which areincorporated herein by reference. Recombinant and mutated forms of G-CSFcan be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;5,528,823; and 5,580,755; the entireties of which are incorporatedherein by reference.

Also provided for use in combination with a compound provided herein, ora derivative thereof, of are native, naturally occurring, andrecombinant proteins. Further encompassed are mutants and derivatives(e.g., modified forms) of naturally occurring proteins that exhibit, invivo, at least some of the pharmacological activity of the proteins uponwhich they are based. Examples of mutants include, but are not limitedto, proteins that have one or more amino acid residues that differ fromthe corresponding residues in the naturally occurring forms of theproteins. Also encompassed by the term “mutants” are proteins that lackcarbohydrate moieties normally present in their naturally occurringforms (e.g., nonglycosylated forms). Examples of derivatives include,but are not limited to, pegylated derivatives and fusion proteins, suchas proteins formed by fusing IgG1 or IgG3 to the protein or activeportion of the protein of interest. See, e.g., Penichet, M. L. andMorrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with a compound providedherein, or a derivative thereof, include monoclonal and polyclonalantibodies. Examples of antibodies include, but are not limited to,trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™),pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®),and G250. The compounds provided herein or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof can also becombined with, or used in combination with, anti-TNF-α antibodies,and/or anti-EGFR antibodies, such as, for example, Erbitux® orpanitumumab.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete, or cause thesecretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used inthe methods and pharmaceutical compositions provided. See, e.g., Emens,L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of acompound provided herein, or a derivative thereof. However, like somelarge molecules, many are believed to be capable of providing asynergistic effect when administered with (e.g., before, after orsimultaneously) a compound provided herein, or a derivative thereof.Examples of small molecule second active agents include, but are notlimited to, anti-cancer agents, antibiotics, immunosuppressive agents,and steroids.

In certain embodiments, the second agent is an HSP inhibitor, aproteasome inhibitor, a FLT3 inhibitor or a TOR kinase inhibitor.

Examples of anti-cancer agents to be used within the methods orcompositions described herein include, but are not limited to: acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole;anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidedimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;busulfan; cactinomycin; calusterone; caracemide; carbetimer;carboplatin; carmustine; carubicin hydrochloride; carzelesin;cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin;cisplatin; cladribine; clofarabine; crisnatol mesylate;cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; omacetaxine; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sorafenib; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs to be included within the methods orcompositions include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; Ara-C ocfosfate; cytolytic factor; cytostatin;dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin;diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib(e.g., Gleevec®); imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O6 benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RH retinamide; rohitukine;romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents particularly useful in the methods orcompositions include, but are not limited to, rituximab, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,Ara-C, doxetaxol, pacilitaxel, vinblastine, IL-2, GM CSF, dacarbazine,vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan,prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin(Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodiumphosphate (Emcyt®), sulindac, and etoposide.

In certain embodiments of the methods provided herein, use of a secondactive agent in combination with a compound provided herein, or aderivative thereof, may be modified or delayed during or shortlyfollowing administration of a compound provided herein, or a derivativethereof, as deemed appropriate by the practitioner of skill in the art.In certain embodiments, subjects being administered a compound providedherein, or a derivative thereof, alone or in combination with othertherapies may receive supportive care including antiemetics, myeloidgrowth factors, and transfusions of platelets, when appropriate. In someembodiments, subjects being administered a compound provided herein, ora derivative thereof, may be administered a growth factor as a secondactive agent according to the judgment of the practitioner of skill inthe art. In some embodiments, provided is administration of a compoundprovided herein, or a derivative thereof, in combination witherythropoietin or darbepoetin (Aranesp).

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with gemcitabine and cisplatinum to subjectswith locally advanced or metastatic transitional cell bladder cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with a second active ingredientas follows: temozolomide to pediatric subjects with relapsed orprogressive brain tumors or recurrent neuroblastoma; celecoxib,etoposide and cyclophosphamide for relapsed or progressive CNS cancer;temodar to subjects with recurrent or progressive meningioma, malignantmeningioma, hemangiopericytoma, multiple brain metastases, relapsedbrain tumors, or newly diagnosed glioblastoma multiforms; irinotecan tosubjects with recurrent glioblastoma; carboplatin to pediatric subjectswith brain stem glioma; procarbazine to pediatric subjects withprogressive malignant gliomas; cyclophosphamide to subjects with poorprognosis malignant brain tumors, newly diagnosed or recurrentglioblastoma multiforms; Gliadel® for high grade recurrent malignantgliomas; temozolomide and tamoxifen for anaplastic astrocytoma; ortopotecan for gliomas, glioblastoma, anaplastic astrocytoma oranaplastic oligodendroglioma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with methotrexate, cyclophosphamide, taxane,abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogenmodulators, estrogen receptor antagonists, and/or PLX3397 (Plexxikon) tosubjects with metastatic breast cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with temozolomide to subjects withneuroendocrine tumors.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with gemcitabine to subjects with recurrent ormetastatic head or neck cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with gemcitabine to subjects with pancreaticcancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with colon cancer in combinationwith ARISA®, avastatin, taxol, and/or taxotere.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with capecitabine and/or PLX4032 (Plexxikon) tosubjects with refractory colorectal cancer or subjects who fail firstline therapy or have poor performance in colon or rectal adenocarcinoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with fluorouracil, leucovorin,and irinotecan to subjects with Dukes C & D colorectal cancer or tosubjects who have been previously treated for metastatic colorectalcancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with refractory colorectal cancerin combination with capecitabine, xeloda, and/or CPT-11.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with capecitabine and irinotecan to subjectswith refractory colorectal cancer or to subjects with unresectable ormetastatic colorectal carcinoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered alone or in combination with interferon alphaor capecitabine to subjects with unresectable or metastatichepatocellular carcinoma; or with cisplatin and thiotepa to subjectswith primary or metastatic liver cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with pegylated interferon alphato subjects with Kaposi's sarcoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with fludarabine, carboplatin,and/or topotecan to subjects with refractory or relapsed or high-riskacute myeloid leukemia.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with liposomal daunorubicin,topotecan and/or cytarabine to subjects with unfavorable karotype acutemyeloblastic leukemia.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with gemcitabine, abraxane,erlotinib, geftinib, and/or irinotecan to subjects with non-small celllung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with carboplatin and irinotecanto subjects with non-small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with doxetaxol to subjects with non-small celllung cancer who have been previously treated with carbo/VP 16 andradiotherapy.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with carboplatin and/ortaxotere, or in combination with carboplatin, pacilitaxel and/orthoracic radiotherapy to subjects with non-small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with taxotere to subjects withstage IIIB or IV non-small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with oblimersen (Genasense®) tosubjects with small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with ABT-737 (AbbottLaboratories) and/or obatoclax (GX15-070) to subjects with lymphoma andother blood cancers.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered alone or in combination with a second activeingredient such as vinblastine or fludarabine to subjects with varioustypes of lymphoma, including, but not limited to, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma or relapsed or refractory lowgrade follicular lymphoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with taxotere, IL-2, IFN,GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine to subjects with varioustypes or stages of melanoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered alone or in combination with vinorelbine tosubjects with malignant mesothelioma, or stage IIIB non-small cell lungcancer with pleural implants or malignant pleural effusion mesotheliomasyndrome.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofmultiple myeloma in combination with dexamethasone, zoledronic acid,palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate,celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combinationthereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with relapsed or refractorymultiple myeloma in combination with doxorubicin (Doxil®), vincristineand/or dexamethasone (Decadron®).

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofovarian cancer such as peritoneal carcinoma, papillary serous carcinoma,refractory ovarian cancer or recurrent ovarian cancer, in combinationwith taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda,paclitaxel, dexamethasone, or a combination thereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofprostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine,irinotecan plus gemcitabine, cyclophosphamide, vincristine,dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel,adriamycin, docetaxel, estramustine, Emcyt, denderon or a combinationthereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofrenal cell cancer, in combination with capecitabine, IFN, tamoxifen,IL-2, GM-CSF, Celebrex®, or a combination thereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofgynecologic, uterus or soft tissue sarcoma cancer in combination withIFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofsolid tumors in combination with celebrex, etoposide, cyclophosphamide,docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combinationthereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with scleroderma or cutaneousvasculitis in combination with celebrex, etoposide, cyclophosphamide,docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combinationthereof.

Also encompassed herein is a method of increasing the dosage of ananti-cancer drug or agent that can be safely and effectivelyadministered to a subject, which comprises administering to the subject(e.g., a human) a compound provided herein, or a derivative thereof.Subjects that can benefit by this method are those likely to suffer froman adverse effect associated with anti-cancer drugs for treating aspecific cancer of the skin, subcutaneous tissue, lymph nodes, brain,lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney,prostate, breast, colorectal, or combinations thereof. Theadministration of a compound provided herein, or a derivative thereof,alleviates or reduces adverse effects which are of such severity that itwould otherwise limit the amount of anti-cancer drug.

In one embodiment, a compound provided herein, or a derivative thereof,is administered orally and daily in an amount ranging from about 0.1 toabout 150 mg, from about 1 to about 50 mg, or from about 2 to about 25mg, prior to, during, or after the occurrence of the adverse effectassociated with the administration of an anti-cancer drug to a subject.In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with specific agents such asheparin, aspirin, coumadin, or G CSF to avoid adverse effects that areassociated with anti-cancer drugs such as but not limited to neutropeniaor thrombocytopenia.

In one embodiment, a compound provided herein, or a derivative thereof,is administered to subjects with diseases and disorders associated withor characterized by, undesired angiogenesis in combination withadditional active ingredients, including, but not limited to,anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, andsteroids.

In another embodiment, encompassed herein is a method of treating,preventing and/or managing cancer, which comprises administering thecompound provided herein, or a derivative thereof, in conjunction with(e.g. before, during, or after) conventional therapy including, but notlimited to, surgery, immunotherapy, biological therapy, radiationtherapy, or other non-drug based therapy presently used to treat,prevent or manage cancer. The combined use of the compound providedherein, or a derivative thereof, and conventional therapy may provide aunique treatment regimen that is unexpectedly effective in certainsubjects. Without being limited by theory, it is believed that thecompound provided herein, or a derivative thereof, may provide additiveor synergistic effects when given concurrently with conventionaltherapy.

As discussed elsewhere herein, encompassed herein is a method ofreducing, treating and/or preventing adverse or undesired effectsassociated with conventional therapy including, but not limited to,surgery, chemotherapy, radiation therapy, hormonal therapy, biologicaltherapy and immunotherapy. A compound provided herein, or a derivativethereof, and other active ingredient can be administered to a subjectprior to, during, or after the occurrence of the adverse effectassociated with conventional therapy.

In one embodiment, the compound provided herein, or a derivativethereof, can be administered in an amount ranging from about 0.1 toabout 150 mg, from about 1 to about 25 mg, or from about 2 to about 10mg orally and daily alone, or in combination with a second active agentdisclosed herein, prior to, during, or after the use of conventionaltherapy.

In certain embodiments, a compound provided herein, or a derivativethereof, and doxetaxol are administered to subjects with non-small celllung cancer who were previously treated with carbo/VP 16 andradiotherapy.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to subjects with various types or stages ofcancer, in combination with an immune oncology drug or a combination ofimmune oncology drugs. In one embodiment, a compound provided herein, ora derivative thereof, is administered to subjects with various types orstages of cancer, in combination with Opdivo, Keytruda, Yervoy or acombination thereof.

6.3.2 Inflammation

As discussed herein, activation of MAPKs is a component of theinflammatory response. Thus, the compounds provided herein, which areMAPK inhibitors via inhibition of Ras and/or a Ras superfamily member,are useful in the treatment of inflammatory diseases.

In one embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that inhibits the function of one or more members of the Rassuperfamily by binding to the GTP binding domain or one or more membersof the Ras superfamily. In one embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that inhibits the function of Rasby binding to a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing inflammatory disease, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with an IC₅₀ of less than 10 μM and a K_(d) of less than10 μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 1 μM and a K_(d) of less than 1 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with an IC₅₀ of less than 500 nM and aK_(d) of less than 500 nM. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with an IC₅₀ of less than 470 nM and a K_(d) of less than 470 nM.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 270 nM and a K_(d) of less than 270 nM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 200 nM and a K_(d) of less than 200 nM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with an IC₅₀ of less than 150 nM and aK_(d) of less than 150 nM. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with an IC₅₀ of less than 100 nM and a K_(d) of less than 100 nM.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with greaterthan 25% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 50% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with greater than 75% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with greaterthan 80% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 85% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with greater than 90% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with greaterthan 95% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 99% inhibition at 20 μM. In one embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatinhibits the function of Rho by binding to a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 10 μM and a K_(d) of less than 10 μM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 1 μM and a K_(d) of less than 1 μM. In another embodiment, providedherein is a method of treating or preventing inflammatory disease, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with an IC₅₀ of less than 500 nM and a K_(d) of less than500 nM. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 270 nM and a K_(d) of less than 270 nM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 200 nM and a K_(d) of less than 200 nM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Rho GTP binding domain with an IC₅₀ of less than 150 nM and aK_(d) of less than 150 nM. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with an IC₅₀ of less than 130 nM and a K_(d) of less than 130 nM.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 100 nM and a K_(d) of less than 100 nM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with greater than 25%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 50% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Rho GTP binding domain with greater than 75% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with greaterthan 80% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 85% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Rho GTP binding domain with greater than 90% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with greaterthan 95% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 99% inhibition at 20 μM. In one embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatinhibits the function of Rac by binding to a Rac GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with an IC₅₀of less than 10 μM and a K_(d) of less than 10 μM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 1 μM and a K_(d) of less than 1 μM. In another embodiment, providedherein is a method of treating or preventing inflammatory disease, whichcomprises administering to a subject a compound that binds to a Rac GTPbinding domain with an IC₅₀ of less than 500 nM and a K_(d) of less than500 nM. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with an IC₅₀of less than 270 nM and a K_(d) of less than 270 nM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 200 nM and a K_(d) of less than 200 nM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Rac GTP binding domain with an IC₅₀ of less than 170 nM and aK_(d) of less than 170 nM. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with an IC₅₀ of less than 150 nM and a K_(d) of less than 150 nM.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with an IC₅₀of less than 100 nM and a K_(d) of less than 100 nM. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with greater than 25%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 50% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Rac GTP binding domain with greater than 75% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with greaterthan 80% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 85% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to a Rac GTP binding domain with greater than 90% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to a Rac GTP binding domain with greaterthan 95% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 99% inhibition at 20 μM.

In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to one or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to three or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to four or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to six or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to seven or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to nine or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to ten or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to eleven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to twelve or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to thirteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to fourteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing inflammatory disease, whichcomprises administering to a subject a compound that binds to fifteen ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to sixteen or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to seventeen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to eighteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to nineteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to twenty or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing inflammatory disease, whichcomprises administering to a subject a compound that binds to twenty-oneor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to twenty-two or moreof Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to twenty-three or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in aRas GTP binding domain.

In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to one or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly 60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146 and Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35,Lys36, Gly 60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing inflammatory disease, whichcomprises administering to a subject a compound that binds to three ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly 60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to four or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly 60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146 and Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to five or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly 60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to seven or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala 18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to eight or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala 18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146 and Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to nine or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala 18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to eleven or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala 18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to twelve or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to fourteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to fifteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to sixteen or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to seventeen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to eighteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to nineteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to twenty or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to twenty-one or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing inflammatorydisease, which comprises administering to a subject a compound thatbinds to twenty-two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to twenty-three or moreof Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to all of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala 18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain.

In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS;KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12;REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment,the Ras is HRAS, KRAS or NRAS. In one embodiment, the Ras is HRAS. Inone embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. Inanother embodiment, the Ras is a mutant form of a Ras described herein.

In another embodiment, provided herein is a method of treating orpreventing inflammatory disease, which comprises administering to asubject a compound that binds to one or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to two or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to three or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to four or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to five or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to six or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to seven or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to eight or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to nine or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to ten or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to eleven or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to twelve or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing inflammatory disease, which comprises administering to asubject a compound that binds to thirteen or more of Gly14, Ala15,Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35,Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to fourteen or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to fifteen or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to sixteen or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds to seventeen or more ofGly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32,Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in aRho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing inflammatory disease, which comprisesadministering to a subject a compound that binds all of Gly14, Ala15,Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35,Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain.

In one embodiment, the Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3;RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3;RAC1; RAC2; RAC3 or CDC42. In one embodiment, the Rho is RHOA. Inanother embodiment, the Rho is a mutant form of a Rho described herein.

In one embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to two or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to three or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to four or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to five or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to six or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to seven or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to eight or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to nine or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to ten or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to eleven or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to twelve or more of Gly12, Ala 13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to thirteen or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to fourteen or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to fifteen or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to sixteen or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to seventeen or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to eighteen or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventinginflammatory disease, which comprises administering to a subject acompound that binds to all of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain.

In one embodiment, the Rho is Rac. In one embodiment the Rac is RAC1;RAC2; RAC3 or RHOG. In one embodiment, the Rac is RAC1. In anotherembodiment, the Rac is a mutant form of a Rac described herein.

In one embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to one or more members of the Rassuperfamily. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Ras. In oneembodiment, the compounds provided herein inhibit GTP binding to Rho. Inone embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Rac. In one embodiment, thecompound for use in the methods and compositions provided herein inhibitGTP binding to Ras and Rho. In one embodiment, the compound for use inthe methods and compositions provided herein inhibit GTP binding to Rasand Rac. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Rho and Rac. In oneembodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Ras, Rho and Rac.

In one embodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 2000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1500 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1250 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 665 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 500 daltons. In anotherembodiment, the compound for use in the methods and compositionsprovided herein contains an oxadiazole, thiadiazole or triazole moiety.In another embodiment, the compound for use in the methods andcompositions provided herein contains a 1,2,4-oxadiazole,1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole,2-(pyridine-2-yl)pyrimidine-4-amine, 2-(pyridine-2-yl)pyrimidine-4-ol,2-(pyridine-2-yl)pyrimidine-4-(1H)-one,2-(pyridin-2-yl)pyrimidin-4(3H)-one,2-(pyridin-2-yl)pyrimidin-4(1H)-imine or2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, thecompound for use in the methods and compositions provided hereincontains a 2-(pyridin-2-yl)pyrimidine-4-amine,2-(pyridin-2-yl)pyrimidine-4-ol, 2-(pyridin-2-yl)pyrimidine-4-(1H)-one,2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one,2-(imidazol-2-yl)pyrimidin-4(1H)-one,2-(imidazol-2-yl)pyrimidin-4-amine,2-(imidazol-2-yl)pyrimidin-4(3H)-imine,2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol,2-(imidazol-4-yl)pyrimidin-4(3H)-one,2-(imidazol-4-yl)pyrimidin-4(1H)-one,2-(imidazol-4-yl)pyrimidin-4-amine,2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

In one embodiment, the inflammatory disease is inflammation-associatedcancer development. As disclosed here, the compounds provided herein areuseful in treatment of cancer. It is well recognized that the immuneinflammatory state serves as a key mediator of the middle stages oftumor development. It is also well known that chronic inflammation canpredispose an individual to cancer. Chronic inflammation is caused by avariety of factors, including bacterial, viral, and parasiticinfections. The longer the inflammation persists, the higher the risk ofassociated carcinogenesis. Anti-inflammatory cancer therapy preventspremalignant cells from turning fully cancerous or impedes existingtumors from spreading to distant sites in the body. Thus, in oneembodiment, the compounds provided herein are useful in treatinginflammatory cancers. Such cancers, and the chronic inflammatoryconditions that predispose susceptible cells to neoplastictransformation, include gastric adenocarcinoma (gastritis),mucosa-associated lymphoid tissue (MALT) lymphoma (gastritis), bladder,liver and rectal carcinomas (schistosomiasis), cholangiocarcinoma andcolon carcinoma (cholangitis), gall bladder cancer (chroniccholecystitis), ovarian and cervical carcinoma (pelvic inflammatorydisease, chronic cervicitis), skin carcinoma (osteomyelitis), colorectalcarcinoma (inflammatory bowel disease), esophageal carcinoma (refluxesophagitis, Barrett's esophagus), bladder cancer (bladder inflammation(cystitis)), mesothelioma and lung carcinoma (asbestosis, silicosis),oral squamous cell carcinoma (gingivitis, lichen planus), pancreaticcarcinoma (pancreatitis, protease mutation), vulvar squamous cellcarcinoma (lichen sclerosis), salivary gland carcinoma (slaladenitis),lung carcinoma (bronchitis) and MALT lymphoma (Sjogren syndrome,Hashimoto's thyroiditis). Shacter, et al., 2002, Oncology, 16(2),217-26.

In certain embodiments, the compounds provided herein are useful intreating inflammatory diseases in the airways, such as nonspecificbronchial hyper-reactivity, chronic bronchitis, cystic fibrosis, andacute respiratory distress syndrome (ARDS).

In certain embodiments, the compounds provided herein are useful intreating asthma and idiopathic lung fibrosis or idiopathic pulmonaryfibrosis (IPF), pulmonary fibrosis, and interstitial lung disease. Asknown to one of skill in the art, the differentiation of fibroblastsinto cell types called myofibroblasts occurs during wound healing, whenthe cells contribute to the deposition of extracellular matrix (ECM) inthe transient process of wound repair. In chronic inflammatory diseasessuch as asthma, pathological tissue remodeling often occurs, and ismediated by the functions of increased numbers of myofibroblasts in thediseased tissue, see Hinz, B. et al. Am J Pathol. 2007; 170: 1807-1816.In certain embodiments, the compounds provided herein prevent or reduceTGF-β-induced myofibroblast differentiation, as measured by theexpression of alpha smooth muscle actin (α-SMA), a hallmark ofmyofibroblast differentiation (Serini, G. and Gabbiani, G. 1999; Exp.Cell Res. 250: 273-283).

In certain embodiments, the compounds provided herein are useful intreating psoriasis, chronic plaque psoriasis, psoriatic arthritis,acanthosis, atopic dermatitis, various forms of eczema, contactdermatitis (includes allergic dermatitis), systemic sclerosis(scleroderma), wound healing, and drug eruption.

In one embodiment, the disease is inflammation, arthritis, rheumatoidarthritis, spondylarthropathies, gouty arthritis, osteoarthritis,juvenile arthritis, and other arthritic conditions, systemic lupuserthematosus (SLE), skin-related conditions, eczema, Sjögren's syndrome,burns, dermatitis, neuroinflammation, allergy pain, autoimmune myositis,neuropathic pain, fever, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis,chronic pulmonary inflammatory disease, and chronic obstructivepulmonary disease (COPD), cardiovascular disease, arteriosclerosis,myocardial infarction (including post-myocardial infarctionindications), thrombosis, congestive heart failure, cardiac reperfusioninjury, as well as complications associated with hypertension and/orheart failure such as vascular organ damage, restenosis, cardiomyopathy,stroke including ischemic and hemorrhagic stroke, reperfusion injury,renal reperfusion injury, ischemia including stroke and brain ischemia,and ischemia resulting from cardiac/coronary bypass, neurodegenerativedisorders, liver disease and nephritis, gastrointestinal conditions,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viraland bacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,acute gout, pneumonitis, myocarditis, pericarditis, myositis, eczema,alopecia, vitiligo, bullous skin diseases, atherosclerosis, depression,retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliarycirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis,thyroiditis, type I diabetes, giant cell arteritis, nephritis includinglupus nephritis, vasculitis with organ involvement such asglomerulonephritis, vasculitis including giant cell arteritis, Wegener'sgranulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasakidisease, Takayasu's Arteritis, vasculitis with organ involvement, acuterejection of transplanted organs. endotoxaemia, systemic inflammatoryresponse syndrome (SIRS), multi-organ dysfunction syndrome, toxic shocksyndrome, acute lung injury, ARDS (adult respiratory distress syndrome),acute renal failure, fulminant hepatitis, burns, acute pancreatitis,postsurgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis,myelitis, SIRS associated with viral infections such as influenza,herpes zoster, herpes simplex, coronavirus or dry eye syndrome (orkeratoconjunctivitis sicca (KCS)).

In certain embodiments, the compounds provided herein are useful intreating neuropathic and nociceptive pain, chronic or acute, such as,without limitation, allodynia, inflammatory pain, inflammatoryhyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabeticneuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthriticpain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain,cancer pain, dental pain, headache, migraine, carpal tunnel syndrome,fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain,post operative pain, post stroke pain, and menstrual pain.

In certain embodiments, the compounds provided herein are useful intreating Alzheimer's disease (AD), mild cognitive impairment (MCI),age-associated memory impairment (AAMI), multiple sclerosis, Parkinson'sdisease, vascular dementia, senile dementia, AIDS dementia, Pick'sdisease, dementia caused by cerebrovascular disorders, corticobasaldegeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease,diminished CNS function associated with traumatic brain injury.

In one embodiment, the compounds provided herein are useful in treatingAlzheimer's disease (AD), ankylosing spondylitis, arthritis(osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis),asthma, atherosclerosis, Crohn's disease, colitis, dermatitis,diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS),systemic lupus, erythematous (SLE), nephritis, Parkinson's disease,ulcerative colitis.

When used for the treatment of inflammatory disease, the compoundsprovided herein may be administered in dosages, routes of administrationand/or to achieve pK profiles as described herein for the treatment ofcancer.

6.3.3 Rasopathies

As discussed herein, Ras signaling is causally implicated inrasopathies. Thus, the compounds provided herein, which inhibit thefunction of one or more members of the Ras superfamily, are useful inthe treatment of rasopathies including neurofibromatosis type 1,Noonan's syndrome, and Costello syndrome.

In one embodiment, provided herein is a method of treating or preventinga rasopathy, which comprises administering to a subject a compound thatinhibits the function of one or more members of the Ras superfamily bybinding to the GTP binding domain or one or more members of the Rassuperfamily. In one embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that inhibits the function of Ras by binding to a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing a rasopathy, which comprises administering to asubject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 10 μM and K_(d) of less than 10 μM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with an IC₅₀ of less than 1 μM and a K_(d) of less than 1μM. In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 500 nM and a K_(d) of less than 500 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with an IC₅₀ of less than 470 nM and a K_(d) of less than470 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 270 nM and a K_(d) of less than 270 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with an IC₅₀ of less than 200 nM and a K_(d) of less than200 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 150 nM and a K_(d) of less than 150 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with an IC₅₀ of less than 100 nM and a K_(d) of less than100 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with greater than 25%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to a Ras GTP binding domain with greaterthan 50% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with greater than 80% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with greater than 85% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to a Ras GTP binding domain with greater than 90%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to a Ras GTP binding domain with greaterthan 95% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 99% inhibition at 20 μM. In one embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that inhibits thefunction of Rho by binding to a Rho GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to a Rho GTP binding domain with an IC₅₀ of less than 10 μM and aK_(d) of less than 10 μM. In another embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with an IC₅₀ of less than 1 μM and a K_(d) of less than 1 μM. Inanother embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 500 nM and a K_(d) of less than 500 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with an IC₅₀ of less than 270 nM and a K_(d) of less than270 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 200 nM and a K_(d) of less than 200 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with an IC₅₀ of less than 150 nM and a K_(d) of less than150 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 130 nM and a K_(d) of less than 130 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with an IC₅₀ of less than 100 nM and a K_(d) of less than100 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with greater than 25%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to a Rho GTP binding domain with greaterthan 50% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with greater than 80% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to a Rho GTP binding domain with greater than 85% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to a Rho GTP binding domain with greater than 90%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to a Rho GTP binding domain with greaterthan 95% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 99% inhibition at 20 μM. In one embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that inhibits thefunction of Rac by binding to a Rac GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to a Rac GTP binding domain with an IC₅₀ of less than 10 μM and aK_(d) of less than 10 μM. In another embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with an IC₅₀ of less than 1 μM and a K_(d) of less than 1 μM. Inanother embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 500 nM and a K_(d) of less than 500 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rac GTPbinding domain with an IC₅₀ of less than 270 nM and a K_(d) of less than270 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 200 nM and a K_(d) of less than 200 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rac GTPbinding domain with an IC₅₀ of less than 170 nM and a K_(d) of less than170 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 150 nM and a K_(d) of less than 150 nM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rac GTPbinding domain with an IC₅₀ of less than 100 nM and a K_(d) of less than100 nM. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with greater than 25%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to a Rac GTP binding domain with greaterthan 50% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to a Rac GTPbinding domain with greater than 80% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to a Rac GTP binding domain with greater than 85% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to a Rac GTP binding domain with greater than 90%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to a Rac GTP binding domain with greaterthan 95% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 99% inhibition at 20 μM.

In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35,Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to two or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120,Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to three or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to four ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to five or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to six ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to seven or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to eight ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to nine or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to ten ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to eleven or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to twelve ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to fourteenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing a rasopathy, which comprises administering to asubject a compound that binds to fifteen or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to sixteen ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to seventeen or more of Ala 11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to eighteenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing a rasopathy, which comprises administering to asubject a compound that binds to nineteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to twenty or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to twenty-one or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to twenty-two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing a rasopathy, which comprises administering toa subject a compound that binds to twenty-three or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain.

In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35,Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to two ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to three or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to four ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to five or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to six ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to seven or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to eight ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to nine or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to ten ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val 29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to eleven or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to twelve ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing a rasopathy, which comprises administering to a subject acompound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to fourteenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing a rasopathy, which comprises administering to asubject a compound that binds to fifteen or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to sixteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to seventeen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to eighteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to nineteenor more of Ala 11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing a rasopathy, which comprises administering to asubject a compound that binds to twenty or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to twenty-one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to twenty-two or moreof Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to twenty-three or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val 29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTPbinding domain.

In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS;KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12;REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment,the Ras is HRAS, KRAS or NRAS. In one embodiment, the Ras is HRAS. Inone embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. Inanother embodiment, the Ras is a mutant form of a Ras described herein.

In another embodiment, provided herein is a method of treating orpreventing a rasopathy, which comprises administering to a subject acompound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18,Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59,Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventing arasopathy, which comprises administering to a subject a compound thatbinds to two or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20,Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120,Lys162 or Mg202 in a Rho GTP binding domain. In another embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to three ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to four ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to five ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to six ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to seven ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to eight ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to nine ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to ten ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to eleven ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to twelve ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to thirteenor more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30,Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162or Mg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to fourteenor more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30,Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162or Mg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to fifteen ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to sixteen ormore of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31,Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 orMg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to seventeenor more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30,Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162or Mg202 in a Rho GTP binding domain. In another embodiment, providedherein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds all of Gly14,Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34,Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTPbinding domain.

In one embodiment, the Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3;RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3;RAC1; RAC2; RAC3 or CDC42. In one embodiment, the Rho is RHOA. Inanother embodiment, the Rho is a mutant form of a Rho described herein.

In one embodiment, provided herein is a method of treating or preventinga rasopathy, which comprises administering to a subject a compound thatbinds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19,Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119,Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In one embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to two ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a highly conserved Rho GTP binding domain. In one embodiment,provided herein is a method of treating or preventing a rasopathy, whichcomprises administering to a subject a compound that binds to three ormore of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33,Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, orMg202 in a Rac GTP binding domain. In one embodiment, provided herein isa method of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to four or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to five or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to six or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to seven or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to eight or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to nine or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to ten or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to eleven or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to twelve or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to thirteen or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to fourteen or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to fifteen or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to sixteen or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to seventeen or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to eighteen or more ofGly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34,Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202in a Rac GTP binding domain. In one embodiment, provided herein is amethod of treating or preventing a rasopathy, which comprisesadministering to a subject a compound that binds to all of Gly12, Ala13,Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59,Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTPbinding domain.

In one embodiment, the Rho is Rac. In one embodiment the Rac is RAC1;RAC2; RAC3 or RHOG. In one embodiment, the Rac is RAC1. In anotherembodiment, the Rac is a mutant form of a Rac described herein.

In one embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to one or more members of the Rassuperfamily. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Ras. In oneembodiment, the compounds provided herein inhibit GTP binding to Rho. Inone embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Rac. In one embodiment, thecompound for use in the methods and compositions provided herein inhibitGTP binding to Ras and Rho. In one embodiment, the compound for use inthe methods and compositions provided herein inhibit GTP binding to Rasand Rac. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Rho and Rac. In oneembodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Ras, Rho and Rac.

In one embodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 2000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1500 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1250 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 665 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 500 daltons. In anotherembodiment, the compound for use in the methods and compositionsprovided herein contains an oxadiazole, thiadiazole or triazole moiety.In another embodiment, the compound for use in the methods andcompositions provided herein contains a 1,2,4-oxadiazole,1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole,2-(pyridine-2-yl)pyrimidine-4-amine, 2-(pyridine-2-yl)pyrimidine-4-ol,2-(pyridine-2-yl)pyrimidine-4-(1H)-one,2-(pyridin-2-yl)pyrimidin-4(3H)-one,2-(pyridin-2-yl)pyrimidin-4(1H)-imine or2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, thecompound for use in the methods and compositions provided hereincontains a 2-(pyridin-2-yl)pyrimidine-4-amine,2-(pyridin-2-yl)pyrimidine-4-ol, 2-(pyridin-2-yl)pyrimidine-4-(1H)-one,2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one,2-(imidazol-2-yl)pyrimidin-4(1H)-one,2-(imidazol-2-yl)pyrimidin-4-amine,2-(imidazol-2-yl)pyrimidin-4(3H)-imine,2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol,2-(imidazol-4-yl)pyrimidin-4(3H)-one,2-(imidazol-4-yl)pyrimidin-4(1H)-one,2-(imidazol-4-yl)pyrimidin-4-amine,2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

6.3.4 Ras-Associated Autoimmune Leukoproliferative Disorder

As discussed herein, Ras has been causally associated withRas-associated autoimmune leukoproliferative disorder. Thus, thecompounds provided herein, which inhibit the function of Ras, are usefulin the treatment of Ras-associated autoimmune leukoproliferativedisorder.

In one embodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder, which comprisesadministering to a subject a compound that inhibits the function of Rasby binding to a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 10 μM and K_(d) of less than 10 μM. In another embodiment, providedherein is a method of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 1 μM and a K_(d) of less than 1 μM. In another embodiment, providedherein is a method of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 500 nM and a K_(d) of less than 500 nM. In another embodiment,provided herein is a method of treating or preventing Ras-associatedautoimmune leukoproliferative disorder, which comprises administering toa subject a compound that binds to a Ras GTP binding domain with an IC₅₀of less than 470 nM and a K_(d) of less than 470 nM. In anotherembodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with an IC₅₀ of less than 270 nM and a K_(d) of less than 270 nM.In another embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with an IC₅₀ of less than 200 nM and a K_(d) of less than200 nM. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to aRas GTP binding domain with an IC₅₀ of less than 150 nM and a K_(d) ofless than 150 nM. In another embodiment, provided herein is a method oftreating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with an IC₅₀ of less than 100 nM and aK_(d) of less than 100 nM. In another embodiment, provided herein is amethod of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with greater than 25%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with greater than 50% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with greater than 75% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 80% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing Ras-associatedautoimmune leukoproliferative disorder, which comprises administering toa subject a compound that binds to a Ras GTP binding domain with greaterthan 85% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with greater than 90%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to a Ras GTP binding domain with greater than 95% inhibition at 20μM. In another embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to a Ras GTPbinding domain with greater than 99% inhibition at 20 μM.

In another embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to one ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to twoor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds tothree or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to fouror more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to fiveor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to sixor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds toseven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds toeight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to nineor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to tenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds toeleven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly60,Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to twelve or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to fourteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to fifteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to sixteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to seventeen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to eighteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to nineteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to twenty or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to twenty-one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to twenty-two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to twenty-three or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 orMg202 in a Ras GTP binding domain.

In another embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to one ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds to twoor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to four or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing Ras-associatedautoimmune leukoproliferative disorder, which comprises administering toa subject a compound that binds to five or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146 and Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder, which comprisesadministering to a subject a compound that binds to six or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain.In another embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to seven ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds toeight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to ten or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146 andLys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing Ras-associatedautoimmune leukoproliferative disorder, which comprises administering toa subject a compound that binds to eleven or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146 and Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to twelve ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing Ras-associated autoimmune leukoproliferative disorder,which comprises administering to a subject a compound that binds tothirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to fourteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to fifteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing Ras-associatedautoimmune leukoproliferative disorder, which comprises administering toa subject a compound that binds to sixteen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder, which comprisesadministering to a subject a compound that binds to seventeen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds to eighteenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to nineteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing Ras-associated autoimmuneleukoproliferative disorder, which comprises administering to a subjecta compound that binds to twenty or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing Ras-associatedautoimmune leukoproliferative disorder, which comprises administering toa subject a compound that binds to twenty-one or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingRas-associated autoimmune leukoproliferative disorder, which comprisesadministering to a subject a compound that binds to twenty-two or moreof Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing Ras-associated autoimmune leukoproliferative disorder, whichcomprises administering to a subject a compound that binds totwenty-three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing Ras-associated autoimmune leukoproliferativedisorder, which comprises administering to a subject a compound thatbinds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146 and Lys147 or Mg202 in a Ras GTPbinding domain.

In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS;KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12;REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment,the Ras is HRAS, KRAS or NRAS. In one embodiment, the Ras is HRAS. Inone embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. Inanother embodiment, the Ras is a mutant form of a Ras described herein.

In one embodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 2000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1500 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1250 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 665 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 500 daltons. In anotherembodiment, the compound for use in the methods and compositionsprovided herein contains an oxadiazole, thiadiazole or triazole moiety.In another embodiment, the compound for use in the methods andcompositions provided herein contains a 1,2,4-oxadiazole,1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole,2-(pyridine-2-yl)pyrimidine-4-amine, 2-(pyridine-2-yl)pyrimidine-4-ol,2-(pyridine-2-yl)pyrimidine-4-(1H)-one,2-(pyridin-2-yl)pyrimidin-4(3H)-one,2-(pyridin-2-yl)pyrimidin-4(1H)-imine or2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, thecompound for use in the methods and compositions provided hereincontains a 2-(pyridin-2-yl)pyrimidine-4-amine,2-(pyridin-2-yl)pyrimidine-4-ol, 2-(pyridin-2-yl)pyrimidine-4-(1H)-one,2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one,2-(imidazol-2-yl)pyrimidin-4(1H)-one,2-(imidazol-2-yl)pyrimidin-4-amine,2-(imidazol-2-yl)pyrimidin-4(3H)-imine,2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol,2-(imidazol-4-yl)pyrimidin-4(3H)-one,2-(imidazol-4-yl)pyrimidin-4(1H)-one,2-(imidazol-4-yl)pyrimidin-4-amine,2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

6.3.5 Fibrotic Disease

As discussed herein, Ras superfamily members are potential targets infibrotic disease treatment. In one embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that inhibits the function of oneor more members of the Ras superfamily by binding to the GTP bindingdomain or one or more members of the Ras superfamily. In one embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that inhibits thefunction of Ras by binding to a Rho GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to a Ras GTP binding domain with an IC₅₀ of less than 10 μMand K_(d) of less than 10 μM. In another embodiment, provided herein isa method of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with an IC₅₀ of less than 1 μM and a K_(d) of less than 1 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 500 nM and a K_(d) of less than 500 nM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRas GTP binding domain with an IC₅₀ of less than 470 nM and a K_(d) ofless than 470 nM. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to a Ras GTP binding domain with anIC₅₀ of less than 270 nM and a K_(d) of less than 270 nM. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to a Ras GTP binding domain with an IC₅₀ of less than 200 nMand a K_(d) of less than 200 nM. In another embodiment, provided hereinis a method of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with an IC₅₀ of less than 150 nM and a K_(d) of less than 150 nM.In another embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with an IC₅₀ of lessthan 100 nM and a K_(d) of less than 100 nM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRas GTP binding domain with greater than 25% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with greater than 50%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRas GTP binding domain with greater than 80% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with greater than 85%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Ras GTP bindingdomain with greater than 90% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRas GTP binding domain with greater than 95% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Ras GTP binding domain with greater than 99%inhibition at 20 μM. In one embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that inhibits the function of Rho by binding toa Rho GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with an IC₅₀ of less than 10 μM and K_(d) of less than 10 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 1 μM and a K_(d) of less than 1 μM. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with an IC₅₀ of less than 500 nM and a K_(d) of less than500 nM. In another embodiment, provided herein is a method of treatingor preventing fibrotic disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with an IC₅₀of less than 270 nM and a K_(d) of less than 270 nM. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to a Rho GTP binding domain with an IC₅₀ of less than 200 nMand a K_(d) of less than 200 nM. In another embodiment, provided hereinis a method of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with an IC₅₀ of less than 150 nM and a K_(d) of less than 150 nM.In another embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rho GTP binding domain with an IC₅₀ of lessthan 130 nM and a K_(d) of less than 130 nM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRho GTP binding domain with an IC₅₀ of less than 100 nM and a K_(d) ofless than 100 nM. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to a Rho GTP binding domain withgreater than 25% inhibition at 20 μM. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to a Rho GTPbinding domain with greater than 50% inhibition at 20 μM. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to a Rho GTP binding domain with greater than 75% inhibitionat 20 μM. In another embodiment, provided herein is a method of treatingor preventing fibrotic disease, which comprises administering to asubject a compound that binds to a Rho GTP binding domain with greaterthan 80% inhibition at 20 μM. In another embodiment, provided herein isa method of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 85% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRho GTP binding domain with greater than 90% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rho GTP binding domain with greater than 95%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rho GTP bindingdomain with greater than 99% inhibition at 20 μM. In one embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that inhibits thefunction of Rac by binding to a Rac GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to a Rac GTP binding domain with an IC₅₀ of less than 10 μMand K_(d) of less than 10 μM. In another embodiment, provided herein isa method of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with an IC₅₀ of less than 1 μM and a K_(d) of less than 1 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 500 nM and a K_(d) of less than 500 nM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRac GTP binding domain with an IC₅₀ of less than 270 nM and a K_(d) ofless than 270 nM. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to a Rac GTP binding domain with anIC₅₀ of less than 200 nM and a K_(d) of less than 200 nM. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to a Rac GTP binding domain with an IC₅₀ of less than 170 nMand a K_(d) of less than 170 nM. In another embodiment, provided hereinis a method of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with an IC₅₀ of less than 150 nM and a K_(d) of less than 150 nM.In another embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rac GTP binding domain with an IC₅₀ of lessthan 100 nM and a K_(d) of less than 100 nM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRac GTP binding domain with greater than 25% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rac GTP binding domain with greater than 50%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 75% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRac GTP binding domain with greater than 80% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rac GTP binding domain with greater than 85%inhibition at 20 μM. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to a Rac GTP bindingdomain with greater than 90% inhibition at 20 μM. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to aRac GTP binding domain with greater than 95% inhibition at 20 μM. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to a Rac GTP binding domain with greater than 99%inhibition at 20 μM.

In another embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to one or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to two ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing fibrotic disease, which comprises administering to asubject a compound that binds to three or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to fouror more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to five or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36,Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to seven or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to eight or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to nine ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing fibrotic disease, which comprises administering to asubject a compound that binds to ten or more of Ala11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds toeleven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to twelve or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to fourteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to fifteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to sixteen ormore of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29,Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117,Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing fibrotic disease, which comprises administering to asubject a compound that binds to seventeen or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to eighteen or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to nineteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to twenty or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147or Mg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to twenty-oneor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to twenty-two or more of Ala11,Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31,Tyr32, Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to twenty-three or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr 35,Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202in a Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to all of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr 35, Lys 36, Gly 60, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain.

In another embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to one or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds to twoor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to three or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to five or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to six or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds toseven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to eight or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17,Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36,Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 ina Ras GTP binding domain. In another embodiment, provided herein is amethod of treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to ten or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to eleven or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds totwelve or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to thirteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to fourteen or more of Ala11, Gly12, Val14, Gly15,Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34,Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146,Lys147 or Mg202 in a Ras GTP binding domain. In another embodiment,provided herein is a method of treating or preventing fibrotic disease,which comprises administering to a subject a compound that binds tofifteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain. In another embodiment, provided herein is a methodof treating or preventing fibrotic disease, which comprisesadministering to a subject a compound that binds to sixteen or more ofAla11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30,Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119,Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to seventeen or more of Ala 11, Gly12, Val14,Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33,Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145,Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to eighteen or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35,Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 orMg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to nineteenor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to twenty or more of Ala11, Gly12,Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32,Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to twenty-one or more of Ala11, Gly12, Val14, Gly15, Lys16,Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35,Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 orMg202 in a Ras GTP binding domain. In another embodiment, providedherein is a method of treating or preventing fibrotic disease, whichcomprises administering to a subject a compound that binds to twenty-twoor more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28,Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61,Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a Ras GTPbinding domain. In another embodiment, provided herein is a method oftreating or preventing fibrotic disease, which comprises administeringto a subject a compound that binds to twenty-three or more of Ala11,Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31,Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120,Ser145, Ala146, Lys147 or Mg202 in a Ras GTP binding domain. In anotherembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18,Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60,Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in a RasGTP binding domain.

In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS;KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12;REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment,the Ras is HRAS, KRAS or NRAS. In one embodiment, the Ras is HRAS. Inone embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. Inanother embodiment, the Ras is a mutant form of a Ras described herein.

In another embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to one or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to two or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to three or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to four or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to five or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to six or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to seven or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to eight or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to nine or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to ten or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to eleven or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to twelve or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to thirteen or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to fourteen or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to fifteen or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to sixteen or more of Gly14, Ala15, Cys16, Gly17,Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37,Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain. Inanother embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to seventeen or more of Gly14, Ala15, Cys16,Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37, Asp59, Lys118, Asp120, Lys162 or Mg202 in a Rho GTP bindingdomain. In another embodiment, provided herein is a method of treatingor preventing fibrotic disease, which comprises administering to asubject a compound that binds all of Gly14, Ala15, Cys16, Gly17, Lys18,Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59,Lys118, Asp120, Lys162 or Mg202 in a Rho GTP binding domain.

In one embodiment, the Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3;RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3;RAC1; RAC2; RAC3 or CDC42. In one embodiment, the Rho is RHOA. Inanother embodiment, the Rho is a mutant form of a Rho described herein.

In one embodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to two or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a highly conserved Rho GTP bindingdomain. In one embodiment, provided herein is a method of treating orpreventing fibrotic disease, which comprises administering to a subjecta compound that binds to three or more of Gly12, Ala13, Gly15, Lys16,Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116,Asp118, Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. Inone embodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to four or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to five or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to six or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to seven or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to eight or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to nine or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to ten or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18,Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to eleven or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to twelve or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to thirteen or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to fourteen or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to fifteen or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to sixteen or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to seventeen or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to eighteen or more of Gly12, Ala13, Gly15, Lys16, Thr17,Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118,Leu119, Cys157, Ala159, or Mg202 in a Rac GTP binding domain. In oneembodiment, provided herein is a method of treating or preventingfibrotic disease, which comprises administering to a subject a compoundthat binds to all of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19,Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119,Cys157, Ala159, or Mg202 in a Rac GTP binding domain.

In one embodiment, the Rho is Rac. In one embodiment the Rac is RAC1;RAC2; RAC3 or RHOG. In one embodiment, the Rac is RAC1. In anotherembodiment, the Rac is a mutant form of a Rac described herein.

In one embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to one or more members of the Rassuperfamily. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Ras. In oneembodiment, the compounds provided herein inhibit GTP binding to Rho. Inone embodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Rac. In one embodiment, thecompound for use in the methods and compositions provided herein inhibitGTP binding to Ras and Rho. In one embodiment, the compound for use inthe methods and compositions provided herein inhibit GTP binding to Rasand Rac. In one embodiment, the compound for use in the methods andcompositions provided herein inhibit GTP binding to Rho and Rac. In oneembodiment, the compound for use in the methods and compositionsprovided herein inhibit GTP binding to Ras, Rho and Rac.

In one embodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 2000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1500 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1250 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 1000 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 750 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 665 daltons. In oneembodiment, the compound for use in the methods and compositionsprovided herein has a molecular weight less than 500 daltons. In anotherembodiment, the compound for use in the methods and compositionsprovided herein contains an oxadiazole, thiadiazole or triazole moiety.In another embodiment, the compound for use in the methods andcompositions provided herein contains a 1,2,4-oxadiazole,1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole,2-(pyridine-2-yl)pyrimidine-4-amine, 2-(pyridine-2-yl)pyrimidine-4-ol,2-(pyridine-2-yl)pyrimidine-4-(1H)-one,2-(pyridin-2-yl)pyrimidin-4(3H)-one,2-(pyridin-2-yl)pyrimidin-4(1H)-imine or2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, thecompound for use in the methods and compositions provided hereincontains a 2-(pyridin-2-yl)pyrimidine-4-amine,2-(pyridin-2-yl)pyrimidine-4-ol, 2-(pyridin-2-yl)pyrimidine-4-(1H)-one,2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one,2-(imidazol-2-yl)pyrimidin-4(1H)-one,2-(imidazol-2-yl)pyrimidin-4-amine,2-(imidazol-2-yl)pyrimidin-4(3H)-imine,2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol,2-(imidazol-4-yl)pyrimidin-4(3H)-one,2-(imidazol-4-yl)pyrimidin-4(1H)-one,2-(imidazol-4-yl)pyrimidin-4-amine,2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

5.4. Compounds for Use in Compositions and Methods

Provided herein are compounds which bind to the GTP binding domain ofone or more Ras superfamily members and compete with the binding of GTPto one or more Ras superfamily members.

Provided herein are compounds which bind to a Ras GTP binding domain andcompete with the binding of GTP to Ras. In one embodiment, the compoundsalso inhibit phosphorylation of MAPK, in particular MAPK1/2, cellularproliferation, secretion of IL-6 or TNF-α cytokines. The compoundsprovided herein are therefore useful in compositions and methods oftreating cancer, inflammatory diseases, Ras-associated autoimmuneleukoproliferative disorder and rasopathies.

Provided herein are compounds which bind to a Rac GTP binding domain andcompete with the binding of GTP to Rac. In one embodiment, the compoundsalso inhibit the MAPK signaling pathway. In one embodiment, thecompounds also inhibit the ROCK signaling pathway. The compoundsprovided herein are therefore useful in compositions and methods oftreating cancer, inflammatory diseases and fibrotic disease.

Provided herein are compounds which bind to a Rho GTP binding domain andcompete with the binding of GTP to Rho. In one embodiment, the compoundsalso inhibit the MAPK signaling pathway. In one embodiment, thecompounds also inhibit the ROCK signaling pathway. The compoundsprovided herein are therefore useful in compositions and methods oftreating cancer, inflammatory diseases and fibrotic disease.

In one embodiment, the compounds provided herein inhibit GTP binding toone or more members of the Ras superfamily. In one embodiment, thecompounds provided herein inhibit GTP binding to Ras. In one embodiment,the compounds provided herein inhibit GTP binding to Rho. In oneembodiment, the compounds provided herein inhibit GTP binding to Rac. Inone embodiment, the compounds provided herein inhibit GTP binding to Rasand Rho. In one embodiment, the compounds provided herein inhibit GTPbinding to Ras and Rac. In one embodiment, the compounds provided hereininhibit GTP binding to Rho and Rac. In one embodiment, the compoundsprovided herein inhibit GTP binding to Ras, Rho and Rac.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula I:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Ia:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, OR³, andNR⁶R⁷;

wherein R^(2a) is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Ia or pharmaceutically acceptable derivatives thereof, wherein:

R^(1a) is selected from the group consisting of H, phenyl, pyridinyl, orfrom one of the following:

R^(2a) is aryl or heteroaryl; and X is NH or S.

In one embodiment, the compound of Formula Ia is:

In another embodiment, the compound of Formula I is a compound ofFormula Ia or pharmaceutically acceptable derivatives thereof, wherein:

R^(1a) is:

R^(2a) is heteroaryl; and X is NH or S.

In one embodiment, the compound of Formula Ia is:

In another embodiment, the compound of Formula I is a compound ofFormula Ib:

or pharmaceutically acceptable derivatives thereof,

wherein R^(2b) is selected from the group consisting of alkyl, aryl,cycloalkyl, heterocyclyl and heteroaryl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached;

p is 0-2; and

X is O or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Ib or pharmaceutically acceptable derivatives thereof, wherein:

R⁶ and R⁷ are independently selected from hydrogen, methyl, isopropyl,phenyl, cyclopropyl, adamantyl, or selected from one of the following:

wherein phenyl is optionally substituted with one, two, or threesubstituents each selected from halogen, and R⁶ and R⁷ are combined toform a cyclic structure including the nitrogen atom to which they areboth attached, wherein the cyclic structure is selected from one of thefollowing:

R and R′ are independently selected from hydrogen and methyl; and

X is O or NH.

In one embodiment, the compound of Formula Ib is:

In another embodiment, the compound of Formula I is a compound ofFormula Ic:

or pharmaceutically acceptable derivatives thereof,

R^(3c) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl orarylcarbonyl;

R^(4c) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached;

p is 0-2; and

X is O or NR⁵.

In another embodiment, the compound of Formula Ic is a compound wherein:

R^(3c) is phenyl or R^(3c), R and R′ are combined to form a cyclicstructure, as shown below

wherein phenyl is optionally substituted with one, two, or threesubstituents each selected from halogen, cyano, and methyl;

R^(4c) is selected from one of the following;

R and R′ are independently selected from hydrogen and methyl, or R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or N-phenyl.

In one embodiment, the compound of Formula Ic is:

In another embodiment, the compound of Formula I is a compound ofFormula Id:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is selected from the group consisting of alkyl, aryl,cycloalkyl, heterocyclyl, heteroaryl and SR⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(4d) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Id wherein:

R^(1d) is selected from one of the following:

R^(4d) is selected from one of the following:

and

X is O or S.

In one embodiment, the compound of Formula Id is:

In another embodiment, the compound of Formula I is a compound ofFormula Ie:

or pharmaceutically acceptable derivatives thereof, wherein:

R^(2e) is selected from the group consisting of aryl, heteroaryl,arylalkyl or heteroarylalkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(4e) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula Ie, the compound of Formula Ie is acompound wherein:

R^(2e) is selected from the group consisting of furyl, pyridinyl,phenyl, and naphthylmethyl,

wherein phenyl is substituted with methyl;

R^(4e) is selected from one of the following:

R⁵ is hydrogen, propyl, cyclohexyl or phenyl; and

p is 0-2.

In one embodiment, the compound of Formula Ie is:

In one embodiment, the compound of Formula I is selected with theproviso that the compound is not

In one embodiment, the compound of Formula Ia is selected with theproviso that the compound is not

In one embodiment, the compound of Formula I is selected with theproviso that if X is NH and R¹ is phenyl, then R² is not pyridyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula II:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment, the compound of Formula II is a compound ofFormula IIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is heterocyclyl or NR⁶R⁷;

wherein R^(2a) is H, aryl, or heteroaryl;

R^(5a) is alkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula Ha, the compound of Formula II is acompound wherein:

R^(1a) is amino, or as depicted below:

wherein R^(2a) is H or pyridinyl;

R^(5a) is isopropyl, or as depicted below:

In one embodiment, the compound of Formula IIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula III:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is O or S; or X is NR, wherein R forms a non-aromatic ring with one ofthe carbon atoms adjacent to the nitrogen on the five-membered ring towhich it is attached.

In another embodiment of Formula III, the compound of Formula III is acompound wherein

R¹ is phenyl or as depicted below:

R² is methyl or as depicted below:

p is 0-2; and

X is O; or X is NR, wherein R forms a seven-membered ring with one ofthe carbon atoms adjacent to the nitrogen on the five-membered ring towhich it is attached.

In one embodiment, the compound of Formula III is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, OR³, andNR⁶R⁷;

wherein R^(2a) is aryl or heteroaryl;

wherein R^(8a) are H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula IIIa, a compound of Formula IIIa is acompound wherein:

R^(1a) is selected from the group consisting of pyridinyl, isoxazolyl,phenyl, benzodioxalyl, quinoxalinyl, pyrolidinonyl, aminoalkyl,benzimidazolyl, benzyl, benzofuranyl, and one of the following:

wherein pyridinyl, isoxazolyl, phenyl, furanyl and benzyl is optionallysubstituted with one or two substituents each selected from methyl,halogen, methoxy, benzodioxalyl, pyridinyl, tetrazolyl;

R^(2a) is pyridinyl;

R^(8a) is hydrogen; and

R⁵ is hydrogen.

In one embodiment, the compound of Formula IIIa is:

In another embodiment of Formula IIIa, a compound of Formula IIIa is acompound wherein:

R^(1a) is selected from the group consisting of:

R^(2a) is pyridinyl;

R⁸¹ is hydrogen; and

R⁵ is hydrogen.

In one embodiment, the compound of Formula IIIa is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is OR³, NR⁵C(O)R⁴ or NR⁶R⁷;

R^(2b) is OR³, aryl or heteroaryl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

R″ and R′″ are independently selected from hydrogen and alkyl, and R″and R′″ are combined to form a cyclic structure including the carbonatom to which they are both attached.

In another embodiment of Formula IIIb, a compound of Formula IIIb is acompound wherein:

R^(1b) is OR³, or phenyl;

R^(2b) is OR³, or as follows:

R³ is phenyl,

wherein phenyl is optionally substituted with one or two substituentseach selected from methoxy, 1,1,1-trifluoropropan-2-ol, and halogen

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁸ is hydrogen; and

R and R′ are hydrogen.

In one embodiment, the compound of Formula IIIb is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is aryl, or heteroaryl;

R^(2c) is SR⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R^(8c) is H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or S.

In another embodiment of Formula III, a compound of Formula IIIc is acompound wherein

R^(1c) is SR⁴, phenyl, or pyridinyl, or thienyl;

wherein phenyl is optionally substituted with one or two substituentsselected from methyl, methoxy, ethoxy, halogen;

R^(2c) is SR⁴, CH₂SR⁴, or selected from the following:

R^(8c) is H or methyl;

R⁴ is selected from the following:

R and R′ are hydrogen; and

X is O or S.

In another embodiment of Formula III, a compound of Formula IIIc is acompound wherein

R^(1c) is SR⁴, phenyl, or pyridinyl, or thienyl;

wherein phenyl is optionally substituted with one or two substituentsselected from methyl, methoxy, ethoxy, halogen;

R^(2c) is SR⁴, CH₂SR⁴, or selected from the following:

R^(8c) is H or methyl;

R⁴ is selected from the following:

R and R′ are hydrogen; and

X is O or S.

In one embodiment, the compound of Formula IIIc is:

In another embodiment, the compound of Formula III is a compound ofFormula IIId:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is alkyl, cycloalkyl, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷;

R^(2d) is aryl or heteroaryl;

R^(8d) is H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula IIId, a compound of Formula IIId is acompound wherein:

wherein R^(1d) is cyclopropyl, phenyl, S(O)₂R⁴, NR⁵C(O)R⁴, or NR⁶R⁷,

wherein phenyl is optionally substituted with one or two substituentseach selected from hydroxyl and CONH₂;

R^(2d) is phenyl or as depicted below:

wherein phenyl is optionally substituted with 1-3 substituents eachselected from methoxy, halogen, methyl, and hydroxyl;

R^(8d) is hydrogen, methyl, or CH₂CH₂CO₂CH₃;

R⁴ is phenyl or selected from one of the following:

wherein phenyl is optionally substituted with two halogens;

R⁵ is hydrogen; and

R⁶ and R⁷ are independently selected from hydrogen, cyclohexyl, and R⁶and R⁷ are combined to form a six-membered cyclic structure includingthe nitrogen atom to which they are both attached.

In another embodiment of Formula IIId, a compound of Formula IIId is acompound wherein:

wherein R^(1d) is cyclopropyl, phenyl, S(O)₂R⁴, NR⁵C(O)R⁴, or NR⁶R⁷,

wherein phenyl is optionally substituted with one or two substituentseach selected from hydroxyl and CONH₂;

R^(2d) is phenyl or as depicted below:

wherein phenyl is optionally substituted with 1-3 substituents eachselected from methoxy, halogen, methyl, and hydroxyl;

R^(8d) is hydrogen, methyl, or CH₂CH₂CO₂CH₃;

R⁴ is phenyl or selected from one of the following:

wherein phenyl is optionally substituted with two halogens;

R⁵ is hydrogen; and

R⁶ and R⁷ are independently selected from hydrogen, cyclohexyl, and R⁶and R⁷ are combined to form a six-membered cyclic structure includingthe nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula IIId is:

In one embodiment, the compound of Formula IIId is:

In another embodiment, the compound of Formula IIId is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is aryl or heteroaryl;

R^(2e) is H or alkyl;

R^(6e) and R^(7e) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached; and

X is O or S.

In another embodiment of Formula IIIe, a compound of Formula IIIe is acompound wherein:

R^(1e) is pyridinyl, phenyl;

wherein phenyl is optionally substituted with one substituent selectedfrom halogen, and ethyl;

R^(2e) is methyl or hydrogen;

R^(6e) and R^(7e) are independently selected from hydrogen or one of thefollowing

and R^(6e) and R^(7e) are combined to form a piperidine including thenitrogen atom to which they are both attached, and this piperidinyl ringis substituted with phenyl; and

X is O or S.

In another embodiment of Formula IIIe, a compound of Formula IIIe is acompound wherein:

R^(1e) is pyridinyl, phenyl;

wherein phenyl is optionally substituted with one substituent selectedfrom halogen, and ethyl;

R^(2e) is methyl or hydrogen;

R^(6e) and R^(7e) are independently selected from hydrogen or one of thefollowing

and R^(6e) and R^(7e) are combined to form a piperidine including thenitrogen atom to which they are both attached, and this piperidinyl ringis substituted with phenyl; and

X is O or S.

In one embodiment, the compound of Formula IIIe is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(2f) is H or alkyl;

R^(4f) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R^(6f) and R^(7f) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula IIIf, a compound of Formula IIIf is acompound wherein

R^(2f) is H or methyl;

R^(4f) is methyl or ethyl; and

R^(6f) and R^(7f) are independently selected from cyclopropyl, ethyl, orone of the following

In one embodiment, the compound of Formula IIIf is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIg:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1g) is aryl or heteroaryl;

R^(6g) and R^(7g) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached; and

R^(8g) is H or alkyl.

In another embodiment of Formula IIIg a compound of Formula IIIg is acompound wherein:

R^(1g) is phenyl, or pyrimidinyl;

wherein phenyl is optionally substituted with one or two substituentseach selected from methoxy, halogen, or propyl;

R^(6g) and R^(7g) are independently selected from hydrogen or one of thefollowing:

R⁶ and R⁷ are combined to form a cyclic structure including the nitrogenatom to which they are both attached, as depicted below:

and

R^(8g) is H.

In one embodiment, the compound of Formula IIIg is:

In one embodiment, the compound of Formula III is selected with theproviso that the compound is not

In one embodiment, the compound of Formula IIId is selected with theproviso that the compound is not

In one embodiment, the compound of Formula III is selected with theproviso that if X is S, then R¹ is not optionally substitutedmorpholino, thiomorpholino, piperinyl, indolyl, pyridyl, thienyl,aminophenyl, phenyl, methoxyphenyl, chloromethyl, amido,imadazothiazolyl, piperizinyl, pyrrolidino, thiazolyl, imidazolyl, orpyrazolyl.

In one embodiment, the compound of Formula IIId is selected with theproviso that R^(1d) is not optionally substituted morpholino,thiomorpholino, piperinyl, indolyl, aminophenyl, chloromethyl, amido,imadazothiazolyl, piperizinyl, pyrrolidino, imidazolyl or pyrazolyl.

In one embodiment, the compound of Formula III is selected with theproviso that if X is S, then R² is not naphthyl or tetrahydronaphthyl.

In one embodiment, the compound of Formula III is selected with theproviso that if X is O and R¹ is phenyl or thienyl, then R⁸ is notmorpholino.

In one embodiment, the compound of Formula III is selected with theproviso that if X is NH and R¹ is heteroaryl, then R⁸ is not morpholino.

In one embodiment, the compound of Formula IIId is selected with theproviso that R^(2d) is not naphthyl or tetrahydronaphthyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula IV:

or pharmaceutically acceptable derivatives thereof,

wherein R¹′ R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is O or NR⁵.

In another embodiment, the compound of Formula IV is a compound ofFormula IVa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(2a) is H or alkyl;

R^(8a) is aryl or heteroaryl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached; and

X is O or NR⁵.

In another embodiment, the compound of Formula IVa is a compound wherein

R^(2a) is H;

R^(8a) is phenyl, pyridinyl, or as shown below

wherein phenyl is optionally substituted with a halogen;

R^(6a) and R^(7a) are independently selected from H, pyridinyl,cyclopropyl, cyclopentyl, or one of the following:

and

X is O or NH, or NCH₃.

In one embodiment, the compound of Formula IVa is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(8b) is H or alkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b) and R^(7b) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or NR⁵.

In another embodiment, Formula IVb is:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(8b) is H or alkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b) and R^(7b) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or NR⁵.

In another embodiment of Formula IVb, a compound of Formula IVb is acompound wherein

R^(1b) is methyl;

R^(8b) is methyl;

R^(6b) and R^(7b) are independently selected from hydrogen, methyl, orone of the following:

R and R′ are hydrogen,

X is O or NR⁵; and

R⁵ is benzyl

wherein benzyl is substituted with a halogen.

In one embodiment, the compound of Formula IVb is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is aryl or heteroaryl;

R^(2c) is H, halo or alkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6c) and R^(7c) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6c) and R^(7c) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

X is O or NR⁵.

In another embodiment of Formula IVc, a compound of Formula IVc is acompound wherein

R^(1c) is phenyl

wherein phenyl is optionally substituted with methyl;

R^(2c) is H or a halogen;

R^(6c) and R^(7c) are independently selected from cyclopropyl or one ofthe following:

and

X is O or NH.

In one embodiment, the compound of Formula IVc is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVd:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is OR^(3a) or NR^(6d)R^(7d);

R^(2d) is H, alkyl or halo;

R^(3d) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl or cycloalkyl;

R^(5d) is aryl, heteroaryl, arylalkyl or heteroarylalkyl;

R^(6d) and R^(7d) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6d) and R^(7d) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

R^(8d) is H or alkyl.

In another embodiment of Formula IVd, a compound of Formula IVd is acompound wherein

R^(1d) is OR^(3d) or NR^(6d)R^(7d);

R^(2d) is H, alkyl or halo;

R^(3d) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl or cycloalkyl;

R^(5d) is aryl, heteroaryl, arylalkyl or heteroarylalkyl;

R^(6d) and R^(7d) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6d) and R^(7d) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

R^(8d) is H or alkyl.

In another embodiment of Formula IVd, a compound of Formula IVd is acompound wherein

R^(1d) is OR^(3d) or NR^(6d)R^(7d);

R^(2d) is H or Br;

R^(3d) is methyl;

R^(5d) is phenyl or as depicted below

wherein phenyl is optionally substituted with one or two substituentseach selected from halogen, methyl, or methoxy;

R^(6d) and R^(7d) are independently selected from hydrogen,pyridinylmethyl, bromophenyl, or as depicted below:

or R^(6d) and R^(7d) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as shown below

and

R^(8d) is H or cyclopropyl.

In one embodiment, the compound of Formula IVd is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is aryl or heteroaryl;

R^(2e) is H or alkyl;

R^(5e) is H or alkyl; and

R^(6e) and R^(7e) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6e) and R^(7e) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached.

In another embodiment of Formula IV, a compound of Formula IVe is acompound wherein

R^(1e) is pyridinyl;

R^(2e) is H;

R^(5e) is H or methyl; and

R^(6e) and R^(7e) are independently selected from hydrogen or thesubstituent as depicted below:

In one embodiment, the compound of Formula IVe is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1f) is H or alkyl;

R^(2f) is aryl, heteroaryl or NR^(6f)R^(7f);

R^(5f) is aryl or heteroaryl;

R^(8f) is H or alkyl;

R^(6f) and R^(7f) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6f) and R^(7f) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached.

In another embodiment of Formula IVf, a compound of Formula IVf is acompound wherein:

R^(1f) is H;

R^(2f) is selected from one of the following:

R^(5f) is phenyl or pyridinyl; and

R^(8f) is H or methyl.

In one embodiment, the compound of Formula IVf is:

In one embodiment, the compound of Formula IV is selected with theproviso that the compound is not

In one embodiment, the compound of Formula IVa is selected with theproviso that the compound is not

In one embodiment, the compound of Formula IV is selected with theproviso that if X is O, then R⁸ is not optionally substitutedmorpholino.

In one embodiment, the compound of Formula IV is selected with theproviso that if X is N-aryl, then R² is not heteroaryl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula V:

or pharmaceutically acceptable derivatives thereof,

wherein R¹′R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷; wherein R² and R⁸ are combined to form a cyclicstructure including the carbon atoms to which they are attached in thefive-membered ring;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is O, S or NR⁵.

In another embodiment the compound of Formula V is a compound of FormulaVa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H or alkyl;

R^(8a) is aryl, heteroaryl, C(O)R⁴ or S(O)_(p)R⁴;

R^(9a) is OR³, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula V, a compound of Formula Va is acompound wherein

R^(1a) is H;

R^(2a) is H;

R^(8a) is phenyl, C(O)R⁴ or S(O)_(p)R⁴;

wherein phenyl is substituted with halogen;

R^(9a) is OR³, NR⁶R⁷, or selected from one of the following

R³ is phenyl,

wherein phenyl is optionally substituted with one or two substituentseach selected from halogen, methoxy and methyl;

R⁴ is selected from the following:

R⁶ and R⁷ are independently selected from ethyl, phenyl, or biphenyl;

R and R′ are H; and

p is 2.

In another embodiment of Formula V, a compound of Formula Va is acompound wherein

R^(1a) is H;

R^(2a) is H;

R^(8a) is phenyl, C(O)R⁴ or S(O)_(p)R⁴;

wherein phenyl is substituted with halogen;

R^(9a) is OR³, NR⁶R⁷, or selected from one of the following

R³ is phenyl,

wherein phenyl is optionally substituted with one or two substituentseach selected from halogen, methoxy and methyl;

R⁴ is selected from the following:

R⁶ and R⁷ are independently selected from ethyl, phenyl, or biphenyl;

R and R′ are H; and

p is 2.

In one embodiment, the compound of Formula Va is:

In another embodiment, the compound of Formula V is a compound ofFormula Vb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(2b) is H or alkyl;

R^(8b) is C(O)R⁴ or S(O)_(p)R⁴;

R^(9b) is aryl, heteroaryl, halo or C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

X is O or NR⁵; and

p is 0-2.

In another embodiment, Formula Vb is:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(2b) is H or alkyl;

R^(8b) is C(O)R⁴ or S(O)_(p)R⁴;

R^(9b) is aryl, heteroaryl, halo or C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

X is O, S or NR⁵; and

p is 0-2.

In another embodiment of Formula Vb, a compound of Formula Vb is acompound wherein

R^(1b) is H, halogen, or COCH₃;

R^(2b) is H, halogen, or COCH₃;

R^(8b) is C(O)R⁴;

R^(9b) is H, halogen, phenyl, or C(O)R⁴;

wherein phenyl is optionally substituted with halogen;

R⁴ is NR⁶R⁷;

R⁶ and R⁷ are independently selected from H, cyclopropyl, thienylmethyl,furanylmethyl, cyclopentyl, methyl, and benzyl;

wherein benzyl is substituted with two methoxy substituents;

X is O, S or NCH₃; and

p is 2.

In one embodiment, the compound of Formula Vb is:

In another embodiment, the compound of Formula V is a compound ofFormula Vc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is H, alkyl or C(O)R⁴;

R^(2c) is H, alkyl or C(O)R⁴;

R^(8c) is H or alkyl;

R^(9c) is OR³, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached.

In another embodiment of Formula Vc, a compound of Formula Vc is acompound wherein

R^(1c) is H or C(O)R⁴;

R^(2c) is H or C(O)R⁴;

R^(8c) is H or methyl;

R^(9c) is OR³;

R³ is selected from one of the following:

R⁴ is methyl; and

R and R′ are H.

In one embodiment, the compound of Formula Vc is:

In another embodiment, the compound of Formula V is a compound ofFormula Vd:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is H, alkyl, aryl or heteroaryl;

R^(2d) is C(O)R⁴;

R^(8d) is NR⁵C(O)R⁴ or N═C(R)NR⁶R⁷;

R^(9d) is H, alkyl, arylalkyl or heteroarylalkyl; wherein R^(1d) andR^(9d) are combined to form a cyclic structure including the carbonatoms to which they are attached in the five-membered ring;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R and R′ are independently selected from hydrogen and alkyl, or R and R′are combined to form a cyclic structure including the carbon atom towhich they are both attached.

In another embodiment of Formula Vd, a compound of Formula Vd is acompound wherein

wherein R^(1d) is H, methyl, or phenyl,

wherein phenyl is optionally substituted with methyl or halogen;

R^(2d) is C(O)R⁴, or as depicted below

R^(8d) is phenyl or NR⁵C(O)R⁴,

wherein phenyl is substituted with propyl;

R^(9d) is H, methyl, benzodioxylphenylmethyl, and wherein R^(1d) andR^(9d) are combined to form a seven-membered cyclic structure includingthe carbon atoms to which they are attached in the five-membered ring;

R⁴ is ethyl, methyl, t-butyl, benzyl or as depicted below

wherein benzyl is optionally substituted with 1-3 substituents eachselected from methoxy

R⁵ is H; and

R and R′ are H.

In another embodiment of Formula Vd, a compound of Formula Vd is acompound wherein

wherein R^(1d) is H, methyl, or phenyl,

wherein phenyl is optionally substituted with methyl or halogen;

R^(2d) is C(O)R⁴, or as depicted below

R^(8d) is phenyl or NR⁵C(O)R⁴,

wherein phenyl is substituted with propyl;

R^(9d) is H, methyl, benzodioxylphenylmethyl, and wherein R^(1d) andR^(9d) are combined to form a seven-membered cyclic structure includingthe carbon atoms to which they are attached in the five-membered ring;

R⁴ is ethyl, methyl, t-butyl, benzyl, p-isopropylphenyl or as depictedbelow

wherein benzyl is optionally substituted with 1-3 substituents eachselected from methoxy

R⁵ is H; and

R and R′ are H.

In one embodiment, the compound of Formula Vd is:

In another embodiment, the compound of Formula V is a compound ofFormula Ve:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is H or alkyl;

R^(2e) is C(O)R⁴;

R^(8e) is H or alkyl;

R^(9e) is H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5e) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula Ve, a compound of Formula Ve is acompound wherein

R^(1e) is H;

R^(2e) is C(O)R⁴;

R^(8e) is H or alkyl;

R^(9e) is H or alkyl;

R⁴ is selected from the following:

R^(5e) is methoxyethyl, propenyl, or cyclohexenylpropyl.

In one embodiment, the compound of Formula Ve is:

In another embodiment, the compound of Formula V is a compound ofFormula Vf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1f) is H or alkyl;

R^(2f) is S(O)_(p)R⁴;

R^(8f) is C(O)R⁴;

R^(9f) is aryl, H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula Vf, a compound of Formula Vf is acompound wherein

R^(1f) is H;

R^(2f) is S(O)_(p)R⁴;

R^(8f) is C(O)R⁴;

R^(9f) is aryl, H or alkyl;

R⁴ is thiomorpholinyl or as depicted below

and

p is 2.

In one embodiment, the compound of Formula Vf is:

In one embodiment, the compound of Formula V is selected with theproviso that the compound is not

In one embodiment, the compound of Formula V is selected with theproviso that if X is S and R⁹ is aryl, then neither R⁸ nor R² ismorpholino.

In one embodiment, the compound of Formula V is selected with theproviso that if X is S and R⁹ is aryl, heteroaryl, oxazolidinonyl,arylcarbonyl, then R⁸ is not morpholino, acyl or an ester.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

A is a substituted or unsubstituted 5 or 6 membered aryl, heteroaryl,carbocyclic or heterocyclic ring.

In one embodiment, the compound of Formula VI is selected with theproviso that the

compound is not

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VIt:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R* is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

A is a substituted or unsubstituted 5 or 6 membered aryl, heteroaryl,carbocyclic or heterocyclic ring.

In one embodiment of Formula VIt,

R¹ is aryl or heteroaryl;

R* is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, orcycloalkyl;

A is a substituted or unsubstituted 5 or 6 membered aryl, heteroaryl,carbocyclic or heterocyclic ring.

In one embodiment of Formula VIt,

R¹ is 2-pyridyl;

R* is methyl;

A is a substituted or unsubstituted thienyl ring.

In one embodiment of Formula VIt,

R¹ is 2-pyridyl;

R* is H or methyl;

A is a substituted or unsubstituted pyrazole ring.

In one embodiment of Formula VIt, the compound is

In another embodiment of Formula VIt, the compound of Formula VIt is acompound of Formula VIt1:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R* is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R⁸ is H, halo, C(O)R⁴ or alkyl;

R⁹ is H, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo,pseudohalo, C(O)R⁴, or S(O)_(p)R⁴; R⁸ and R⁹ can be combined to form acyclic structure including the carbon atoms to which they are bothattached, wherein the cyclic structure is a cycloalkyl orheterocycloalkyl;

p is 0-2.

In one embodiment of Formula VIt1,

R¹ is aryl or heteroaryl;

R* is H or alkyl.

R⁸ is H or C(O)R⁴;

R⁹ is selected from the group consisting of methyl, but-2-yl,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In one embodiment, the compound of Formula VIt1 is:

In one embodiment of Formula VIt1,

R¹ is aryl or heteroaryl;

R* is hydrogen or alkyl.

R⁸ and R⁹ are combined to form a cyclic structure including the carbonatoms to which they are both attached, wherein the cyclic structure is acycloalkyl or heterocycloalkyl.

In one embodiment, the compound of Formula VIt1 is:

In another embodiment of Formula VIt, the compound of Formula VIt is acompound of Formula VIt2:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R* is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R⁸ is H, halo, C(O)R⁴ or alkyl;

R⁹ is H, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo,pseudohalo, C(O)R⁴, or S(O)_(p)R⁴; R⁸ and R⁹ can be combined to form acyclic structure including the carbon atoms to which they are bothattached, wherein the cyclic structure is a cycloalkyl orheterocycloalkyl;

p is 0-2.

In one embodiment of Formula VIt2,

R¹ is aryl or heteroaryl;

R* is hydrogen or alkyl.

R⁸ and R⁹ are combined to form a cyclic structure including the carbonatoms to which they are both attached, wherein the cyclic structure is acycloalkyl or heterocycloalkyl.

In one embodiment, the compound of Formula VIt2 is:

In another embodiment of Formula VIt2, a compound of Formula VIt2 is acompound wherein

R¹ is N-methyl-imidazolyl,

R⁸ is pyridyl, phenyl, or

R⁹ is phenyl;

R* is H, CH₃, —CH₂CH₂OEt or —CH₂CH₂NEt₂.

In one embodiment, the compound of Formula VIt2 is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is aryl or heteroaryl;

R^(8a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In one embodiment of Formula VIa, a compound of Formula VIa is acompound wherein

R^(1a) is aryl or heteroaryl;

R^(8a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIa, a compound of Formula VIa is acompound wherein

R^(1a) is pyridinyl,

wherein pyridinyl is optionally substituted with one or two substituentseach selected from OR³;

R³ is difluoroethyl;

R^(8a) is H, methyl, phenyl, C(O)R⁴;

R^(9a) is H, phenyl, methyl, thienyl, ethyl, furanyl, or butyl, whereinphenyl is optionally substituted with a substituent selected fromhalogen or methoxy;

R⁴ is —NR⁶R⁷; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In one embodiment, the compound of Formula VIa is:

In one embodiment, the compound of Formula VIa is selected with theproviso that

the compound is not

In another embodiment, the compound of Formula VI is a compound ofFormula

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a1) is aryl, heteroaryl or NR⁶R⁷;

R^(8a1) is H or alkyl;

R^(9a1) is H, alkyl, alkenyl, carbocyclic, halo, pseudohalo,trifluoromethyl, cyano, or C(O)NR⁶R⁷; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is aryl, heteroaryl or NR⁶R⁷;

R^(8a1) is H, aryl, or alkyl;

R^(9a1) is H, alkyl, alkenyl, halo or pseudohalo; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is aryl, heteroaryl or NR⁶R⁷;

R^(8a1) is H or alkyl;

R^(9a1) is alkyl, alkenyl, halo or pseudohalo, wherein the alkyl groupis not CH₃; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is pyridinyl or NH₂,

R^(2a1) is H or methyl;

R^(9a1) is H or methyl.

In one embodiment, the compound of Formula VIa1 is:

In one embodiment, the compound of Formula VIa1 is:

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is pyridinyl,

R^(2a1) is H or methyl;

R^(9a1) is fluoro, bromo, chloro or iodo.

In one embodiment, the compound of Formula VIa1 is:

In one embodiment, the compound of Formula VIa1 is:

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is 2-pyridinyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein R^(1a1) is methoxypyridinyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is 2-pyridyl;

R^(8a1) is H or Ph;

R^(9a1) is carbocyclic, halo, trifluoromethyl, cyano, or C(O)NR⁶R⁷;

R⁶ is H or alkyl;

and R⁷ is alkyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is 2-pyridyl;

R^(8a1) is H or methyl;

R^(9a1) is carbocyclic, halo, trifluoromethyl, cyano, or C(O)NR⁶R⁷;

R⁶ is H or alkyl;

and R⁷ is alkyl.

In another embodiment, the compound of Formula VI is a compound ofFormula VIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is alkyl, aryl, heteroaryl, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(8b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷; or R^(8b) and R^(9b) are combined to form a cyclic structureincluding the carbon atoms to which they are attached in thefive-membered ring;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(5b) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb, a compound of Formula VIb is acompound wherein

R^(1b) is pyridinyl, S(O)_(p)R⁴,

R^(8b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷; wherein R^(8b) and R^(9b) are combined to form a cyclic structureincluding the carbon atoms to which they are attached in thefive-membered ring;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is depicted below

R^(5b) is hydrogen or ethyl;

p is O.

In one embodiment, the compound of Formula VIb is:

In another embodiment of Formula VIb, a compound of Formula VIb is acompound wherein

R^(1b) is pyridyl, N-methyl-imidazolyl or NH₂;

R^(8b) is phenyl, pyridyl, C(O)R⁴,

R^(9b) is H, Br, phenyl, CH₃,

R⁴ is

and

R^(5b) is hydrogen.

In one embodiment, the compound of Formula VIb is:

In one embodiment, the compound of Formula VIb is:

In one embodiment, the compound of Formula VIb is selected with theproviso that the compound is not

In another embodiment, the compound of Formula VIb is a compound ofFormula VIb 1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b1) is alkyl, aryl, heteroaryl, or NR⁶R⁷;

R^(8b1) is H or alkyl;

R^(9b1) is aryl, heteroaryl, heterocyclyl, halo, pseudohalo, C(O)R⁴, orS(O)_(p)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb1,

R^(1b1) is aryl, heteroaryl, or NR⁶R⁷;

R^(8b1) is C(O)R⁴;

R^(9b1) is aryl, heteroaryl, heterocyclyl, halo, pseudohalo, C(O)R⁴, orS(O)_(p)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridyl;

R^(8b1) is H or alkyl;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, fluoro, chloro,iodo, C(O)R⁴, or S(O)_(p)R⁴, wherein the heteroaryl group is not asubstituted pyrazole;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl or NH₂;

R^(8b1) is H;

R^(9b1) is aryl, heteroaryl, halo, heterocyclyl or C(O)R⁴;

R⁴ is —NR⁶R⁷; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H or methyl;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, C(O)NR⁶R⁷,wherein the heteroaryl group is not a substituted pyrazole; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocycloalkyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, C(O)NR⁶R⁷,wherein the heteroaryl group is not a substituted pyrazole; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocycloalkyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula VIb1, R^(1b1) is alkyl, aryl,heteroaryl, or NR⁶R⁷;

R^(8b1) is H or alkyl;

R^(9b1) is alkyl or cycloalkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb1,

R^(1b1) is aryl, heteroaryl, or NR⁶R⁷;

R^(8b1) is C(O)R⁴;

R^(9b1) is alkyl or cycloalkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridyl;

R^(8b1) is H or alkyl;

R^(9b1) is alkyl or cycloalkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl or NH₂;

R^(8b1) is H;

R^(9b1) is alkyl or cycloalkyl;

R⁴ is —NR⁶R⁷; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H or methyl;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, C(O)NR⁶R⁷,wherein the heteroaryl group is not a substituted pyrazole; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocycloalkyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H;

R^(9b1) is alkyl or cycloalkyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocycloalkyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is NH₂;

R^(8b1) is H;

R^(9b1) is Br,

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is Br,

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein R^(1b1) is 2-pyridyl.

In one embodiment, the compound of Formula VIb1 is:

In one embodiment, the compound of Formula VIb1 is:

In one embodiment, the compound of Formula VIb1 is:

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H, methyl, —COOH or —COOCH₃;

R^(9b1) is selected from the group consisting of: H, methyl, cyclobutyl,—CO₂CH₃,

piperidin-4-ylmethyl, piperidin-3-ylmethyl, 2-chlorophenyl,

In one embodiment, the compound of Formula VIb1 is:

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(9b1) is H, methyl, —COOH or —COOCH₃;

R^(8b1) is selected from the group consisting of:

In one embodiment, the compound of Formula VIb1 is:

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H, t-butyl or CH₃;

R^(9b1) is Br,

In one embodiment, the compound of Formula VIb1 is:

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is N-methyl-imidazolyloryrimidinyl;

R^(8b1) is H or CH₃;

R^(9b1) is Ph,

In one embodiment, the compound of Formula VIb1 is:

In some embodiments of Formula VIb1, R^(1b1) is pyridyl, imidazolyl,N-methyl-2-imidazolyl, N-methyl-4-imdidazolyl, 2-pyrimidinyl or4-pyrimidinyl.

In one embodiment, the compound of Formula VIb1 is:

In one embodiment, the compound of Formula VIb1 is selected with theproviso

that the compound is not

In one embodiment, the compound of Formula VIb1 is selected with theproviso that if R^(9b1) is aryl and R^(8b1) is H, then R^(1b1) is not asaturated heterocyclic group.

In some embodiments of Formula VIb1, R^(1b1) is imidazolyl.

In another embodiment, the compound of Formula VI is a compound ofFormula

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is aryl, or heteroaryl; and

R may consist of 0-6 substituents independently selected from H oralkyl.

In another embodiment of Formula VIc, a compound of Formula VIc is acompound wherein

R^(1c) is pyridinyl; and

R is H.

In one embodiment, the compound of Formula VIc is:

In another embodiment, the compound of Formula VI is a compound ofFormula VId:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is aryl or heteroaryl;

R^(5d) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; and

X is CH or N.

In another embodiment of Formula VId, a compound of Formula VId is acompound wherein

R^(1d) is pyridinyl;

R^(5d) is hydrogen or phenyl,

wherein phenyl is substituted with CF₃;

X is CH or N.

In one embodiment, the compound of Formula VId is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is S(O)_(p)R⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5e) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

R may consist of 0-4 substituents independently selected from H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷.

In another embodiment of Formula VIe,

R^(1e) is heteroaryl, S(O)_(p)R⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5e) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

R may consist of 0-4 substituents independently selected from H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷.

In another embodiment, the compound of Formula VI is a compound ofFormula VIe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is S(O)_(p)R⁴ or NR⁶R⁷;

R⁴ is

R^(5e) is H, methoxyethyl or CH₃OCH₂(CH₃)CH—;

R⁶ and R⁷ are independently selected from hydrogen or as depicted below

p is 0; and

R is H or halogen.

In one embodiment, the compound of Formula VIe is:

In one embodiment, the compound of Formula VIe is a compound

wherein R^(1e) is heteroaryl; and

R is H, fluoro, bromo, chloro, or iodo.

In one embodiment, the compound of Formula VIe is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1f) is aryl, or heteroaryl; and

R^(2f) is H, —C(O)R, —C(O)OR, —S(O)₂R, —S(O)R or alkyl,

wherein R is aryl, heteroaryl or alkyl.

In another embodiment of Formula VIf, a compound of Formula VIf is acompound wherein

R^(1f) is 2-pyridyl; and

R^(2f) is —C(O)R,—C(O)OR or SO₂R,

wherein R is aryl, heteroaryl or alkyl.

In another embodiment of Formula VIf, a compound of Formula VIf is acompound wherein

R^(1f) is 2-pyridyl; and

R^(2f) is —C(O)R,

wherein R is aryl, heteroaryl or alkyl.

In another embodiment of Formula VIf, a compound of Formula VIf is acompound wherein

R^(1f) is pyridinyl; and

R^(2f) is H,

In one embodiment, the compound of Formula VIf is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIg:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1g) is aryl or heteroaryl; and

R^(5g) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl.

In another embodiment of Formula VIg, a compound of Formula VIg is acompound wherein

R^(1g) is 2-pyridyl; and

R^(5g) is aryl, heteroaryl, heterocyclyl, cycloalkyl, CH₂C(O)R, whereinR is NH₂, NHalkyl, N(alkyl)₂, piperidine, OH or Oalkyl.

In another embodiment of Formula VIg, a compound of Formula VIg is acompound wherein

R^(1g) is pyridinyl; and

R^(5g) is hydrogen, phenyl, pyridyl or

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2.

In another embodiment of Formula VII, a compound of Formula VII is acompound wherein

R^(1a) is pyridinyl;

R^(2a) is —Oaryl, Oalkyl or —OH;

R^(8a) is Oaryl, COOalkyl or unsubstituted or substituted aryl.

In one embodiment, the compound of Formula VII is:

In one embodiment, the compound of Formula VII is selected with theproviso that the compound is not

In another embodiment, the compound of Formula VII is a compound ofFormula VIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is alkyl, cycloalkyl, aryl or heteroaryl;

R^(2a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R^(8a) is H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2.

In another embodiment of Formula VIIa,

R^(1a) is CH₂NR⁶R⁷;

R^(2a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R^(8a) is H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2.

In one embodiment of Formula VIIa, the compound of Formula VIIa is

or its HCl salt.

In another embodiment of Formula VIIa, a compound of Formula VIIa is acompound wherein

R^(1a) is pyridinyl;

R^(2a) is selected from one of the following:

R^(8a) is methyl.

In another embodiment of Formula VIIa, a compound of Formula VIIa is acompound wherein

R^(1a) is pyridinyl;

R^(2a) is selected from one of the following:

and

R^(8a) is methyl.

In one embodiment, the compound of Formula VIIa is:

In another embodiment of Formula VIIa, a compound of Formula VIIa is acompound wherein

R^(1a) is pyridinyl or imidazolyl;

R^(2a) is —Oalkyl;

R^(8a) is H or alkyl.

In one embodiment, the compound of Formula VIIa is:

In one embodiment, the compound of Formula VIIa is:

In another embodiment of Formula VIIa, a compound of Formula VIIa is acompound wherein

R^(1a) is aminoalkyl or aminocycloalkyl;

R^(2a) is —Oalkyl;

R^(8a) is H or alkyl.

In one embodiment, the compound of Formula VIIa is:

In one embodiment, the compound of Formula VIIa is selected with theproviso that the compound is not

In one embodiment, the compound of Formula VIIa is selected with theproviso

that the compound is not

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VIIt:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R* is alkyl, aryl or heteroaryl.

p is 0-2.

In one embodiment, the compound of Formula VIIt is

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VIIIa or Formula VIIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R¹′ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

A is a substituted or unsubstituted 5 or 6 membered aryl, heteroaryl,carbocyclic or heterocyclic ring.

In one embodiment of Formula VIIIa, A is a pyrazole ring.

In one embodiment, the compound of Formula VIIIa is

In another embodiment, the compound of Formula VIIIa is a compound ofFormula VIIIa1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a1) is H, aryl or heteroaryl;

R^(2a1) is H, alkyl, alkoxy or aryloxy;

R^(8a1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9a1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or NR⁶R⁷;

R^(5a1) is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula VIIIa1, a compound of Formula VIIIa1 isa compound wherein

R^(1a1) is H;

R^(2a1) is H;

R^(8a1) is phenyl,

wherein phenyl is substituted with methoxy;

R^(9a1) is phenyl,

wherein phenyl is substituted with methoxy;

R^(5a1) is depicted below:

In one embodiment, the compound of Formula VIIIa1 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b1) is H, alkyl, aryl or heteroaryl;

R^(8b1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9b1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b1) and R^(7b1) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

p is 0-2.

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H, methyl or phenyl;

R^(9b1) is H, alkyl, alkenyl, alkynyl, substituted aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R^(6b1) and R^(7b1) are combinedto form a cyclic structure including the nitrogen atom to which they areboth attached; and

wherein NR^(6b1)R^(7b1) is not NHMe, NHEt, NHn-Pr, NHbenzyl orNH-2-phenethyl; and

wherein NR^(6b1)R^(7b1) is not morpholine when R^(8b1) and R^(9b1) areboth hydrogen; and

p is 0-2.

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H;

R^(9b1) is substituted aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,C(O)NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R^(6b1) and R^(7b1) are combinedto form a cyclic structure including the nitrogen atom to which they areboth attached; and

wherein NR^(6b1)R^(7b1) is not NHMe, NHEt, NHn-Pr, NHCH₂CH₂OH, NHbenzyloptionally substituted on the phenyl ring, or NH-2-phenethyl optionallysubstituted on the phenyl ring; and

wherein NR^(6b1)R^(7b1) is not morpholine when R^(8b1) and R^(9b1) areboth hydrogen.

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is H, methyl, or pyridinyl;

R^(8b1) is H or methyl;

R^(9b1) is H or phenyl,

wherein phenyl is optionally substituted with one or two substituentsselected from methoxy;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R^(6b1) and R^(7b1) are independently selected from H, methyl,hydroxypropyl, methoxypropyl, hydroxyethyl, morpholinylethyl,furanylmethyl, or one of the following:

or

R^(6b1) and R^(7b1) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as depicted below

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H, methyl or phenyl;

R^(9b1) is H, bromo or phenyl; and

NR^(6b1)R^(7b1) is selected from

wherein NR^(6b1)R^(7b1) is not morpholine when R^(8b1) and R^(9b1) areboth hydrogen.

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H, methyl or phenyl;

R^(9b1) is —C(O)NR⁶R⁷; and is selected from

NR^(6b1)R^(7b1) is selected from

In another embodiment of Formula VIIIb 1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is H;

R^(6b1) and R^(7b1) are independently selected from H.

In one embodiment, the compound of Formula VIIIb 1 is:

In another embodiment of Formula VIIIb 1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl or methoxypyridinyl;

R^(8b1) is H;

R^(9b1) is H, bromo, chloro, cyano, trifluoromethyl or phenyl; and

NR^(6b1)R^(7b1) is

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb 1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is H; and

R^(6b1) and R^(7b1) are independently selected from H,

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb 1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

NR^(6b1)R^(7b1) is morpholino or —N(CH₂CH₂OCH₃)₂; and

R^(9b1) is —C(O)NR⁶R⁷; and is selected from

In one embodiment, the compound of Formula VIIIb 1 is:

In another embodiment of Formula VIIIb 1, a compound of Formula VIIIb1is a compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

NR^(6b1)R^(7b1) is NH₂, morpholino or —N(CH₂CH₂OCH₃)₂; and

R^(9b1) is —C(O)NR⁶R⁷; and is selected from

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb 1, a compound of Formula VIIIb 1is a compound wherein

R^(1b1) is pyridinyl, N-methyl-imidazolyl;

R^(8b1) is pyridinyl, phenyl, pyrimidinyl, methyl, tetrahydropyranyl;

NR^(6b1)R^(7b1) is

morpholino, —NHCH₂CH₂OCH(CH₃)₂, —NHCH(CH₃)CH₂OCH₃, —NHCH(CH₃)CH₂OH,—N(CH₃)CH₂CH₂OCH₃, —NHCH₂CH₂OCF₃, —NHCH₂CH(CH₃)OH, —NHCH₂CH₂CH₂OH,—NHCH₂CH₂CH₂OCH₃, —NHCH₂CH₂O-cPr, —NHCH₂CH₂OCH₂CH₃ or —NHCH₂CH₂OCH₃; and

R^(9b1) is pyridyl or phenyl.

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb2:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b2) is H, aryl or heteroaryl;

R^(6b2) and R^(7b2) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b1) and R^(7b2) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

p is 0-2; and

R may consist of 0-6 substituents independently selected from H oralkyl.

In another embodiment, the compound of Formula VIIIb is a compoundwherein

R^(1b2) is pyridinyl;

R^(6b2) and R^(7b2) are independently selected from one of thefollowing:

or

R^(6b2) and R^(7b2) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as depicted below:

R is H.

In one embodiment, the compound of Formula VIIIb2 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb3:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b3) is H, aryl or heteroaryl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b3) and R^(7b3) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b3) and R^(7b3) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

p is 0-2; and

R may consist of 0-4 substituents independently selected from H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷.

In another embodiment, the compound of Formula VIIIb3 is a compoundwherein:

R^(1b3) is thienyl;

R^(6b3) and R^(7b3) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as depicted below

and

R is H.

In one embodiment, the compound of Formula VIIIb3 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb4:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b4) is H, alkyl, aryl or heteroaryl;

R^(8b4) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9b4) is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, C(O)R⁴, or S(O)_(p)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b4) and R^(7b4) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b4) and R^(7b4) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment of Formula VIIIb4, a compound of Formula VIIIb4 is acompound wherein

wherein R^(1b4) is 2-pyridyl;

R^(8b4) is H;

R^(9b4) is CH₂CONHR, wherein R is H, alkyl, aryl, arylakyl, heteroaryl;

NR^(6b4)R^(7b4) is a morpholine ring; and

p is 0-2.

In one embodiment of Formula VIIIb4, a compound of Formula VIIIb4 is acompound wherein

R^(1b4) is pyridinyl;

R^(8b4) is H;

R^(9b4) is CH₂CONHR, wherein R is H,

NR^(6b4)R^(7b4) is

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb5:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b5) is H, alkyl, aryl or heteroaryl;

R^(8b5) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9b5) is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, C(O)R⁴, or S(O)_(p)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b5) and R^(7b5) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b5) and R^(7b5) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment, the compound of Formula VIIIb5 is a compound wherein

R^(1b5) is pyridinyl;

R^(6b5) and R^(7b5) are each H;

R^(8b5) is H or methyl;

R^(9b5) is H or COOCH₃.

In one embodiment, the compound of Formula VIIIb is:

In one embodiment, the compound of Formula VIIIb1 is:

In some embodiments of Formula VIIIb 1, R^(1b1) is pyridyl, imidazolyl,N-methyl-2-imidazolyl, N-methyl-4-imdidazolyl, 2-pyrimidinyl or4-pyrimidinyl.

In one embodiment, the compound of formula VIIIb is selected with theproviso that if A is a substituted or unsubstituted phenyl or thienylring, and R⁶ is H; then R⁷ is not 4-pyridyl, pyrimidinyl,chloropyridinyl or indazole.

In one embodiment, the compound of formula VIIIb1 is selected with theproviso that if R⁶ is H; then R⁷ is not 4-pyridyl, pyrimidinyl,chloropyridinyl or indazole.

In one embodiment, the compound of formula VIIIb3 is selected with theproviso that if R⁶ is H; then R⁷ is not 4-pyridyl, pyrimidinyl,chloropyridinyl or indazole.

In one embodiment, the compound of Formula VIIIb is selected with theproviso that the compound is not

In one embodiment, the compound of Formula VIIIb1 is selected with theproviso that the compound is not

In one embodiment, the compound of Formula VIIIb1 is selected with theproviso that NR^(6b1)R^(7b1) is not ═NNH₂.

In one embodiment, the compound of Formula VIIIb1 is selected with theproviso that R^(8b1) and R^(9b1) do not combine to form a cyclic ringstructure.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula IXa or Formula IXb:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl and alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In one embodiment, the compound of Formula IXa is

In another embodiment, the compound of Formula IXa is a compound ofFormula IXa1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a1) is aryl or heteroaryl;

R^(2a1) is H or alkyl;

R^(8a1) is alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylamino, alkylamino,arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylamino,heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyland alkylsulfonyl; or R^(6a1) and R^(7a1) are combined to form a cyclicstructure including the nitrogen atom to which they are both attached.

In another embodiment of Formula IXa1,

R^(1a1) is aryl or heteroaryl;

R^(2a1) is H or alkyl;

R^(8a1) is H or alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylamino, alkylamino,arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylamino,heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyland alkylsulfonyl; or R^(6a1) and R^(7a1) are combined to form a cyclicstructure including the nitrogen atom to which they are both attached.

In one embodiment of Formula IXa1, R^(1a1) is aryl or heteroaryl;

R^(2a1) is H or alkyl;

R^(8a1) is alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylamino, alkylamino,arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylamino,heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyland alkylsulfonyl; or R^(6a1) and R^(7a1) are combined to form a cyclicstructure including the nitrogen atom to which they are both attached.

In one embodiment of Formula IXa1, R^(1a1) is 2-pyridyl;

R^(2a1) is H or alkyl;

R^(8a1) is alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, C(O)R,wherein R is alkyl, cycloalkyl, or heterocycloalkyl.

In one embodiment, R^(1a1) is

R^(2a1) is H or methyl;

R^(8a1) is methyl, ethyl, or trifluoromethyl;

R^(6a1) and R^(7a1) are independently selected from H,

or R^(6a1) and R^(7a1) are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment of Formula IXa1, R^(1a1) is

R^(2a1) is H or methyl;

R^(8a1) is H;

R^(6a1) and R^(7a1) are independently selected from H,

In one embodiment, the compound of Formula IXa1 is:

In one embodiment, the compound of Formula IXa1 is:

In one embodiment, R^(1a1) is

R^(2a1) is H or methyl;

R^(8a1) is methyl, ethyl, or trifluoromethyl;

R^(6a1) and R^(7a1) are independently selected from H,

In one embodiment, the compound of Formula IXa1 is:

In another embodiment, the compound of Formula IXb is a compound ofFormula IXb1:

or pharmaceutically acceptable derivatives thereof,

wherein each R^(5b1) is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl orR⁶ and R⁷ are combined to form a cyclic structure including the nitrogenatom to which they are both attached.

In one embodiment, each R^(5b1) is methyl or

R^(6b1) and R^(7b1) are combined to form a piperidine structureincluding the nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula IXb1 is:

In one embodiment, the compound of Formula IXa is selected with theproviso that if R¹ is heteroaryl, then NR⁶R⁷ is not morpholino.

In one embodiment, the compound of Formula IXa1 is selected with theproviso that if R^(1a) is heteroaryl, then NR^(6a)R^(7a) is notmorpholino.

In one embodiment, the compound of Formula IXa is selected with theproviso that if R¹ is morpholino, then NR⁶R⁷ is not NH₂.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula X:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

p is 0-2.

In another embodiment, the compound of Formula X is a compound ofFormula Xa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H or halo;

R^(8a) is H or alkyl;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl orR^(6a) and R^(7a) are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In one embodiment, R^(1a) is H, methyl, or trifluoromethyl;

R^(2a) is H or Br;

R^(8a) is H, methyl, or trifluoromethyl;

R^(6a) and R^(7a) are independently selected from hydrogen,

or R^(6a) and

R^(7a) are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula Xa is:

In one embodiment, the compound of Formula X is selected with theproviso that if R¹ is methyl and NR⁶R⁷ is NH₂, then R⁸ is not aryl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

p is 0-2.

In another embodiment, the compound of Formula XI is a compound ofFormula XIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5a) is H, aryl or heteroaryl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached.

In one embodiment, R^(1a) is H or methyl;

R^(2a) is

and

R^(5a) is Ph.

In one embodiment, the compound of Formula XIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

p is 0-2.

In another embodiment, the compound of Formula XII is a compound ofFormula XIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is alkyl or NR⁶R⁷;

R^(2a) is H or alkyl;

R^(8a) is H or alkyl;

R^(9a) is H or R⁶′R⁷′NC(O)alkyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

R⁶′ and R⁷′ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl; or R⁶′ and R⁷′are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In one embodiment, R^(1a) is methyl,

R^(2a) is H;

R^(8a) is methyl or trifluoromethyl; and

R^(9a) is H,

In one embodiment, the compound of Formula XIIa is:

In one embodiment, the compound of Formula XII is selected with theproviso that the compound is not

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XIII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸, R⁹, R¹⁰ and R¹¹ are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

p is 0-2.

In another embodiment, the compound of Formula XIII is a compound ofFormula XIIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H or alkyl;

R^(8a) is H or alkyl;

R^(9a) is H or alkyl;

R^(10a) is aryl, heteroaryl or C(O)R⁴;

R^(11a) is H, -alkylOR³ or C(O)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached.

In another embodiment, R^(1a) is H or alkyl;

R^(2a) is H, OR^(3a) or alkyl;

R^(8a) is H or alkyl;

R^(9a) is H or alkyl;

R^(10a) is aryl, heteroaryl or C(O)R⁴;

R^(11a) is H, -alkylOR³ or C(O)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached.

In one embodiment, R^(1a) is H;

R^(2a) is H or

R^(8a) is H;

R^(9a) is H;

R^(10a) is

and

R^(11a) is H,

In one embodiment, the compound of Formula XIIIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XIV:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is S or NR⁵.

In another embodiment, the compound of Formula XIV is a compound ofFormula XIVa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(8a) and R^(9a) are independently selected from thegroup consisting of H, alkyl or halo;

R^(2a) is H, alkyl, halo, C(O)R⁴ and S(O)_(p)R⁴;

R^(10a) is heterocyclyl, -alkylNR⁶R⁷ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is S or NR⁵.

In one embodiment, R^(1a), R^(8a) and R^(9a) are H;

R^(2a) is H or

R^(10a) is

R⁵ is H, methyl, n-propyl,

and

X is S or NR⁵.

In one embodiment, R^(1a), R^(8a) and R^(9a) are H;

R^(2a) is H, —CO(O)Et, or

R^(10a) is

R⁵ is H, methyl, n-propyl.

and

X is S or NR⁵.

In one embodiment, the compound of Formula XIVa is:

In another embodiment, the compound of Formula XIVa is:

In one embodiment, the compound of formula XIV is selected with theproviso that R^(m) is not morpholinomethyl, piperidinylmethyl,methylpiperizinylmethyl, morpholino-CH(CH₃)—, piperidinyl-CH(CH₃)—,methylpiperizinyl-CH(CH₃)—; and X is not NR⁵ if R⁵ is aryloxyalkyl orarylalkyl.

In another embodiment, the disease to be treated with the compounds offormula XIV is not a retinal tumor.

In one embodiment, the compound of formula XIVa is selected with theproviso that R^(10a) is not morpholinomethyl, piperidinylmethyl,methylpiperizinylmethyl, morpholino-CH(CH₃)—, piperidinyl-CH(CH₃)—,methylpiperizinyl-CH(CH₃)—; and X is not NR⁵ if R⁵ is aryloxyalkyl orarylalkyl.

In another embodiment, the disease to be treated with the compounds offormula XIVa is not a retinal tumor.

In one embodiment, the compound of Formula XIV is selected with theproviso that the compound is not

In one embodiment, the compound of Formula XIVa is selected with theproviso that the compound is not

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVa or Formula XVb:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl orheteroarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached;

p is 0-2; and

Ar is aryl or heteroaryl.

In another embodiment, the compound of Formula XVa is a compound ofFormula XVa1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H, aryl or heteroaryl; and

R^(5a) is alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl orheteroarylcarbonyl.

In one embodiment, R^(1a) is H, phenyl; and

R^(5a) is

In one embodiment, the compound of Formula XVa1 is:

In another embodiment, the compound of Formula XVb is a compound ofFormula XVb1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H, aryl or heteroaryl;

R^(5a) is alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl orheteroarylcarbonyl; and

Ar is aryl or heteroaryl.

In one embodiment, R^(1a) is

R^(5a) is

and

Ar is

In one embodiment, the compound of Formula XVb1 is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2;

each R and R′ are independently selected from H, alkyl, or cycloalkyl;and

Ar is aryl or heteroaryl.

In another embodiment, the compound of Formula XVI is a compound ofFormula XVIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a) and R^(9a) are independently selectedfrom the group consisting of H, alkyl and halo;

R^(5a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6a) and R^(7a) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

p is 0-2;

each R and R′ are independently selected from H, alkyl, or cycloalkyl;and

Ar is aryl or heteroaryl.

In one embodiment, R^(1a), R^(2a), R^(8a) and R^(9a) are independentlyselected from the group consisting of H, and F;

R^(5a) is cyclopropyl or

each R and R′ are H or methyl; and

Ar is

In one embodiment, the compound of Formula XVIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo,OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment, the compound of Formula XVII is a compound ofFormula XVIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a), R^(12a), R^(13a),R^(14a) and R^(15a) are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R^(11a) is NR^(6a)R^(7a);

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R^(6′) is arylalkyl or heteroarylalkyl;

R^(7′) is H or alkyl, and R⁶ and R⁷ are combined to form a cyclicstructure including the nitrogen atom to which they are both attached;and

p is 0-2.

In one embodiment, R^(1a), R^(2a), R^(8a), R^(9a), R^(10a), R^(12a),R^(13a), R^(14a) and R^(15a) are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R^(11a) is NR^(6a)R^(7a);

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R⁶ is arylalkyl or heteroarylalkyl;

R⁷ is H or alkyl, and R⁶ and R⁷ are combined to form a cyclic structureincluding the nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment, wherein R^(1a), R_(2a), R^(8a), R^(9a), R^(10a),R^(12a), R^(13a), R^(14a) and R^(15a) are independently selected fromthe group consisting of H, methyl, F, trifluoromethyl, or OEt; and

R^(11a) is

In one embodiment, the compound of Formula XVIIa is:

In another embodiment, the compound of Formula XVII is a compound ofFormula XVIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a) are independentlyselected from the group consisting of H, alkyl, halo, and OR³;

R^(11a), R^(12a), R^(13a), R^(14a) and R^(15a) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴,S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R^(6′) is arylalkyl or heteroarylalkyl;

R^(7′) is H or alkyl, and R⁶ and R⁷ are combined to form a cyclicstructure including the nitrogen atom to which they are both attached;and

p is 0-2.

In one embodiment, R^(1b), R^(2b), R^(8b), R^(9b), R^(10b) areindependently selected from the group consisting of H, alkyl, halo, andOR³;

R^(11b), R^(12b), R^(13b), R^(14b) and R^(15b) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴,S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R⁶ is arylalkyl or heteroarylalkyl;

R⁷ is H or alkyl, and R⁶ and R⁷ are combined to form a cyclic structureincluding the nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment, wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a) areindependently selected from the group consisting of H, F, OMe, OPh, CF₃,and

and

R^(11a), R^(12a), R^(13a), R^(14a) and R^(15a) are independentlyselected from the group consisting of H, CF₃,

In one embodiment, wherein R^(1b), R^(2b), R^(8b), R^(9b), R^(10b) areindependently selected from the group consisting of H, F, OMe, OPh, CF₃,and

and

R^(11b), R^(12b), R^(13b), R^(14b) and R^(15b) are independentlyselected from the group consisting of H, CF₃,

In one embodiment, the compound of Formula XVIIb is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVIII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

X is S(O)p or CR₂, wherein each R is independently selected fromhydrogen and lower alkyl.

In another embodiment, the compound of Formula XVIII is a compound ofFormula XVIIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a), R^(9a) and R^(10a) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, nitro, halo, pseudohalo, OR³,C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6a) and R^(7a) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment, R^(1a), R^(2a), R^(8a), R^(9a) and R^(10a) areindependently selected from the group consisting of H, CH₃, Cl, CF₃,NO₂, OCH₃,

R⁶ and R⁷ are independently selected from hydrogen, CH₃, CH₂CH₃cyclopropyl,

and R⁶ and R⁷ are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment, R^(1a), R^(2a), R^(8a), R^(9a) and R^(10a) areindependently selected from the group consisting of H, CH₃, Cl, CF₃,NO₂, OCH₃,

R^(6a) and R^(7a) are independently selected from hydrogen, CH₃, CH₂CH₃cyclopropyl,

and R^(6a) and

R^(7a) are combined to form including the nitrogen atom to which theyare both attached.

In one embodiment, the compound of Formula XVIIIa is:

In another embodiment, the compound of Formula XVIII is a compound ofFormula XVIIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b), R^(2b), R^(8a), R^(9b) and R^(10b) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, nitro, halo, pseudohalo, OR³,C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b) and R^(7b) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

R and R′ are independently selected from hydrogen and lower alkyl; and

p is 0-2.

In another embodiment, R^(1b), R^(2b), R^(8b), R^(9b) and R^(10b) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, nitro, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl,or R^(6b) and R^(7b) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached;

R and R′ are independently selected from hydrogen and lower alkyl; and

p is 0-2.

In one embodiment, R^(1b), R^(2b), R^(8a), R^(9b) and R^(10b) areindependently selected from the group consisting of H, OCH₃, SCF₃;

R^(6b) and R^(7b) are independently selected from CH₃ and

R and R′ are H.

In another embodiment, R^(1b), R^(2b), R^(8b), R^(9b) and R^(10b) areindependently selected from the group consisting of H, OCH₃, SCF₃;

R^(6b) and R^(7b) are independently selected from CH₃ and

R and R′ are H.

In one embodiment, the compound of Formula XVIIIb is:

In one embodiment, the compound of Formula XVIII is selected with theproviso that if X is CH₂, then NR⁶R⁷ is not indolinone orbenzoimidazolone.

In one embodiment, the compound of Formula XVIIIb is selected with theproviso that if R and R′ are both H, then NR⁶R⁷ is not indolinone orbenzoimidazolone.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XIX:

or pharmaceutically acceptable derivatives thereof,

wherein R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, oxo, OR³, C(O)R⁴,S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment, the compound of Formula XIX is a compound ofFormula XIXa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a) and R^(9a) are independently selectedfrom the group consisting of H, alkyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, oxo and C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5a) is alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,heteroarylcarbonyl, aryl sulfonyl, heteroarylsulfonyl,cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In one embodiment, R^(1a), R^(2a), R^(8a) and R^(9a) are independentlyselected from the group consisting of H, cyclopentyl, cyclohexyl, NO₂,

and

R^(5a) is

In another embodiment, R^(1a), R^(2a), R^(8a) and R^(9a) areindependently selected from the group consisting of H, cyclopentyl,cyclohexyl, oxo,

and

R^(5a) is

In one embodiment, the compound of Formula XIXa is:

In one embodiment, the compound of formula XIX is selected with theproviso that the compound does not contain a hydrazide, a macrocycle, athienopyridine or a thienopyrimidine.

In another embodiment, the disease to be treated with the compounds offormula XIX is not hepatocellular cancer.

In one embodiment, the compound of formula XIXa is selected with theproviso that the compound does not contain a hydrazide, a macrocycle, athienopyridine or a thienopyrimidine.

In another embodiment, the disease to be treated with the compounds offormula XIXa is not hepatocellular cancer.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XX:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In another embodiment, the compound of Formula XX is a compound ofFormula XXa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is OR³, S(O)_(p)R⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R^(2a) is alkyl, aryl or heteroaryl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and lower alkyl; and

p is 0-2.

In one embodiment, R^(1a) is CH₃, Bn,

R^(2a) is CH₃, CH₂CH₃, t-Bu, Ph,

and

R and R′ are independently selected from hydrogen and CH₃.

In one embodiment, the compound of Formula XXa is:

In another embodiment, the compound of Formula XX is a compound ofFormula XXb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is alkyl, arylalkyl or heteroarylalkyl;

R^(2b) is aryl, heteroaryl, or C(R)(R′)NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R and R′ are independently selected from hydrogen and lower alkyl.

In one embodiment, R^(1b) is CH₃,

and

R^(2b) is

In one embodiment, the compound of Formula XXb is:

In another embodiment, the compound of Formula XX is a compound ofFormula XXc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is aryl or heteroaryl; and

R^(2b) is heterocyclyl.

In one embodiment, R^(1b) is

and

R^(2b) is

In one embodiment, the compound of Formula XXc is:

In one embodiment, the compound of Formula XX is selected with theproviso that if R¹ is pyridyl, then R² is not phenyl.

In one embodiment, the compound of Formula XX is selected with theproviso that if R² is pyridyl, then R¹ is not phenyl or cyclohexyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XXI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R⁹ is H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2; and

Ar is aryl or heteroaryl.

In another embodiment, the compound of Formula XXI is a compound ofFormula XXIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a) and R^(8a) are H or alkyl;

R^(9a) is H or alkyl;

R^(5a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; and

Ar is aryl or heteroaryl.

In one embodiment, R^(1a), R^(2a) and R^(8a) are H;

R⁹ is H or CH₃;

R^(5a) is Bn,

and

Ar is Ph,

In one embodiment, the compound of Formula XXIa is:

In one embodiment, the compound of Formula XXI is selected with theproviso that if Ar is pyridyl, then R⁵ is not phenyl.

In one embodiment, the compound of Formula XXIa is selected with theproviso that if Ar is pyridyl, then R⁵ is not phenyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XXII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R⁶ and R⁷are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

n is 0 or 1;

p is 0-2; and

each Ar is independently selected from aryl or heteroaryl.

In another embodiment, the compound of Formula XXII is a compound ofFormula XXIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H;

n is 0 or 1; and

each Ar is independently selected from aryl or heteroaryl.

In another embodiment, Formula XXIIa is:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H;

n is 0 or 1; and

each Ar is independently selected from aryl or heteroaryl.

In one embodiment, R^(1a) is H or CH₃;

R^(2a) is H;

n is 0 or 1; and

Ar is independently selected from Ph,

In one embodiment, R^(1a) is H or CH₃;

R^(2a) is H;

n is 0 or 1; and

Ar is independently selected from

In one embodiment, the compound of Formula XXIIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are selected from the group consisting of thefollowing:

In certain embodiments, the compound for use in the compositions andmethods provided herein is

6.5. Synthesis of the Compounds

The compounds provided herein may be obtained from commercial sources orreadily synthesized by methods well known to those of skill in the art.

6.5.1 Synthetic Procedures

Amide

A vial was charged with 0.6 mmol of Reagent B, 1.6 mmol of DIPEA, anddry acetonitrile (1 mL). To the stirred reaction mixture 0.5 mmol ofReagent A (in case of amine salt, an additional 1.5 equivalent amount ofDIPEA was added to the reaction mixture), and 0.72 mmol of2-chloro-N-methylpyridinium iodide was added. The reaction vial wasplaced into a water bath and left at 100° C. for 6 hrs. Reaction mixturewas cooled to room temperature and diluted by 6 mL of water. Then thevial was sonicated. If crystalline precipitate was formed it wasfiltered off. In case an oily product was formed the vial was leftovernight, then the water layer was removed and 2-propanol (1 mL) wasadded to cause the crystallization. The precipitate was filtered, washedtwice with a sodium carbonate solution, and then washed with methanol.Purification of the final compounds was performed via preparative HPLCon Agilent 1260 Infinity systems equipped with DAD and mass-detectors.Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm withSunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used.Solvents used were deionized Water (phase A) and HPLC-grade Methanol(phase B). Preset chromatography gradient methods were chosen on thebasis of compound properties.

A vial was charged with 0.6 mmol of Reagent B, a solvent (1 mL of asolution of 200 g HOBt in 1 L of DMF), 0.57 mmol of Reagent A (in caseof using amine salt, an additional 1.5 equivalent amount of DIPEA wasadded to the reaction mixture to transfer the amine to base form) and0.66 mmol of EDC. In case the reaction mixture becomes highly viscous0.5 mL of DMF were added. In case the reaction mixture was a homogeneousthe it was kept at room temperature for 72 hrs. Otherwise the reactionmixture was sonicated at room temperature for 5 days. Reaction mixturewas diluted with 6 mL of 1% sodium phosphate water solution. Then thevial was sonicated. In case a crystalline precipitate was formed it wasfiltered off. In case an oily product was formed the product wasdissolved in methanol and precipitated by an addition of 4% hydrochloricacid. Alternatively 2-propanol (1 mL) was mixed with the crude productand the mixture was sonicated. Then the solution was diluted with 5%aqueous sodium hydrogen carbonate (the procedure repeated 2-3 times ifnecessary). Purification of the compounds was performed via preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

A vial was charged with 0.57 mmol of Reagent B and dry DMF (1 mL). Tothe stirred reaction mixture 0.57 mmol of N,N-carbodiimidazole wasadded. After 1 hr of stirring the vial was open and the reaction mixturewas left for 2 hrs in a drying oven at 60° C. Then 0.52 mmol of ReagentA (in case of amine salt, an additional 1.5 equivalent amount of DIPEAwas added to the reaction mixture) was added, the vial was firmlyclosed, and the reaction mixture was stirred. The reaction vial wasplaced into a water bath and left at 100° C. for a time specified on thevial label. Reaction mixture was cooled to room temperature and waterwas added until the vial was full. Then the vial was sonicated. In casea crystalline precipitate was formed the vial was passed to thefiltration. In case an oily product was formed the vial was leftovernight, then the water layer was removed and 2-propanol (1 mL) wasadded to cause the crystallization. The precipitate was filtered, washedtwice with a sodium carbonate solution, and then washed with awater/2-propanol (1:1) solution. Purification of the compounds wasperformed via preparative HPLC on Agilent 1260 Infinity systems equippedwith DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm,19 mm×10 mm was used. Solvents used were deionized Water (phase A) andHPLC-grade Methanol (phase B). Preset chromatography gradient methodswere chosen on the basis of compound properties.

In a large vial 1.2 mmol of a Reagent B was loaded, then 1 mmol of aReagent A (in case of amine salt, an additional 1.5 equivalent amount ofDIPEA was added to the reaction mixture) and polymeric EDC (3 mmol, MW833 g/mol) were added. 10 ml of solvent (30 g of pentafluorophenol in 1L of dichloromethane) were added, the vial was closed and mixture wasstirred. The vial was shaked continuously for 72 hours using shaker.Reaction mixture was filtered, collecting filtrate in a big tared vial.Precipitated polymer was preserved. Filtrate was evaporated, residue wasweighed. If amount of the residue was low, then a small portion ofmethanol (about 5 ml) was added to the precipitated polymer and shakedfor 4 hours. Methanol solution was filtered to the vial with driedresidue after the first filtration. Filtrate was evaporated again andthe residue was passed to the chromatography. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Oxndinznie Synthesis

0.6 mmol of Reagent B was loaded into a small vial. 0.6 mL of solvent (asolution of 200 g N-oxybenzotriazole in 1 L of DMF) and 0.6 mmol ofReagent A (in case of amine salt, an additional 1.5 equivalent amount ofDIPEA was added to the reaction mixture) were added to it. 0.9 mmol ofEDC was added to the reactionary mixture after this. If the reactionarymixture was homogeneous it should be kept at the room temperature for 72hours. If not, it should be sonicated for 5 days at the room temperaturewithout any serious heating. 0.6 mmol of TEA was added after this andthe vial with the reactionary mixture was put into bain-marie and heatedat 100 C for a time indicated on the vial label (ca. 3 h). Thereactionary mixture was cooled than and 3 mL of CH2CL2 with water inamount enough to fill the vial was added to it. The organic layer waswashed out with water two times. All water was removed after this andthe product was forwarded for the further drying. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

1.6 mmol of Reagent A was loaded in small vial then 2 ml of ethanol, 2.4mmol of hydroxylamine and 3.2 mmol of TEA were added. If the reactionmixture is not homogenous then another portion of ethanol (1 mL) wasadded, stirred for 3-4 hours on shaker and left at rt overnight. Then itwas heated at 80° C. for 3 hours and the solvent was removed underreduced pressure. The solid residue was dissolved in 1 mL of solvent (1mL of a solution of 200 g HOBt in 1 L of DMF), 1.6 mmol of Reagent B and2.4 mmol of CDI and sonicated for 3 days at rt. In case the reactionmixture was viscous additional 1 mL of DMF was added. Then 1.6 mmol ofTEA were added and the vial was heated at 100° C. for 3 hours. Thereaction mixture was cooled, diluted with 3 ml of water and extracted by3 mL of CH₂Cl₂. The organic layer was washed out with water two times.All water was removed after this and the product was forwarded for thefurther drying. Purification of the compounds was performed viapreparative HPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Amino/Amide Synthesis

1.6 mmol of Reagent A (in case of amine salt, an additional 1.5equivalent amount of DIPEA was added to the reaction mixture), 1.7 mmolof Reagent B, were added to 1 mL of a solution of 200 gBenzotriazole-N-oxide in 1 L of DMF. To the stirred mixture 1.9 mmol ofEDC was then added. The resulting mixture was stirred at roomtemperature for 72 hours. The mixture was then diluted with 5 ml of 1%sodium phosphate solution, treated with ultrasound. After that 2 mL ofHCl solution in 1,4-dioxane was added and the mixture was treated withultrasound for 4 hours. The solid or oily crude product formed wasisolated and purified via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Oxypyrimidine Synthesis

A small vial was charged with 1.6 mmol of Reagent A, 1.6 mmol of ReagentB and 1 ml of 4M dioxane solution of HCl. The vial was heated at 100° C.for 4 h. In case reaction mixture was too viscous additional 0.5 ml ofdioxane were added. Then it was diluted with 3 ml of water and extractedby 3 mL of CHCl₃. Organic layer was washed with water (2*2 mL), driedand evaporated. The solid residue was purified by preparativechromatography. In case of reasonable amount of residue formed duringextraction procedure it was separated from solution and purified bypreparative chromatography. Purification of the compounds was performedvia preparative HPLC on Agilent 1260 Infinity systems equipped with DADand mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Enamine Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 ml of DMF and 1.6 mmolof Reagent B. The reaction mixture was stirred and heated at 100° C. for4 h. Then it was cooled to rt. In case of residue formed it was filteredoff and purified by preparative chromatography. Otherwise the reactionmixture was diluted with 3 ml of water and extracted by 3 mL of CHCl₃.The organic layer was washed with water (2*2 mL), dried and evaporated.The solid residue was purified by preparative HPLC on Agilent 1260Infinity systems equipped with DAD and mass-detectors. Waters SunfireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 PrepGuard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Halogen Displacement: Carbon-Oxygen/Nitrogen/Sulfur Bond Formation

To a stirred solution containing 0.6 mmol of Reagent A (in case of aminesalt, an additional 1.5 equivalent amount of DIPEA was added to thereaction mixture), 0.72 mmol of DIPEA, 80 mg of potassium iodide in 1 mLof DMF and 0.6 mmol of Reagent B was added. The reaction mixture wasallowed to stir on a boiling water bath for ca. 5 min. Upon a completedissolution of the reagents the stirred reaction mixture was heated onthe water bath for the time specified on the vial label. The reactionmixture was triturated with an excess of deionized water and sonicateduntil a crystalline precipitate was formed. In case the trituration withwater did not cause the product precipitation 1 mL of 2-propanol withthe subsequent sonication were applied instead. The precipitate wasfiltered, washed twice with methanol, and dried. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), dry DMF (2 mL), and 1.4 mmol of DIPEA. To the stirred reactionmixture 0.6 mmol of Reagent B was added. The firmly closed reaction vialwas placed into a water bath and the reaction mixture was stirred at100° C. until a complete dissolution of the reaction component occurs.Then the homogeneous reaction mixture was heated in the water bath at100° C. for 6 hrs. The vial was passed to the polymer scavengerpurification. The solvent was removed under reduced pressure. Ethylacetate (10 mL) and then wet anion resin (5 g) were added to theresidue. The stirred mixture was heated in a water bath at 70° C. for 6hrs. Then the resin was filtered off. The solution was transferred intoa pre-weighted vial and the solvent was removed under reduced pressure.Purification of the compounds was performed via preparative HPLC onAgilent 1260 Infinity systems equipped with DAD and mass-detectors.Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm withSunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used.Solvents used were deionized Water (phase A) and HPLC-grade Methanol(phase B). Preset chromatography gradient methods were chosen on thebasis of compound properties.

Amine Synthesis: Mannich Reaction

A vial was charged with 1.6 mmol of Reagent A, 2 ml of methanol and 6.4mmol of formaline. If the solution was not homogenous additional 0.5 mLof methanol were added. The reaction mixture was sonicated for 1 h. Then1.6 mmol of Reagent B were added and sonicated for another 1 h. In caseof substantial amount of residue formed it was filtered off, washed byiPrOH (water then iPrOH if TEA is present in the reaction mixture) andpurified by preparative HPLC. Otherwise the reaction mixture was dilutedwith 3 mL of water and extracted by 3 mL of CHCl₃. The organic layer waswashed with water (2*2 mL), dried and evaporated. The solid residue waspurified by preparative HPLC on Agilent 1260 Infinity systems equippedwith DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm,19 mm×10 mm was used. Solvents used were deionized Water (phase A) andHPLC-grade Methanol (phase B). Preset chromatography gradient methodswere chosen on the basis of compound properties.

Oxamide Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 mL of acetonitrile, 2.9mmol of DIPEA and 1.6 mmol of ethyl chlorooxalate. The reaction mixturewas stirred for 30 min at rt and 1.76 mmol of Reagent B were added. Thevial was heated at 100° C. for 6 h. The reaction mixture was cooled tort, diluted with 3 mL of water and extracted by 3 mL of CHCl₃. Theorganic layer was washed with water (2*2 mL), dried and evaporated. Thesolid residue was purified by preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Ether Synthesis

A small vial was charged with 0.6 mmol of Reagent A (in case of aminesalt, an additional 1.5 equivalent amount of DIPEA was added to thereaction mixture), followed by 80 mg of potassium iodide in 0.7 mL DMF,and then 0.6 mmol of Reagent B. After stirring 1 mL 4M solution of KOHin methanol was added, the vial was closed tightly and shaked. Next thevial was sonicated for 24 h at the temperature no more than 35° C. Afterthat the vial was filled with chloroform to the brim. After stirring theorganic layer was washed twice with water and dried. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Bicyclic Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 mL of pyridine and 1.6mmol of Reagent B, stirred. Then 6.4 mmol of Me₃SiCl were added and thereaction mixture was stirred and heated at 100° C. for 8 h. Then it wascooled to rt and 1.9 mmol of TEA were added and the vial was heated foranother 30 min at 100° C. Then the reaction mixture was diluted with 3ml of water and extracted by 3 mL of CHCl₃. The organic layer was washedwith water (3*2 mL), dried and evaporated. The solid residue waspurified by preparative HPLC on Agilent 1260 Infinity systems equippedwith DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm,19 mm×10 mm was used. Solvents used were deionized Water (phase A) andHPLC-grade Methanol (phase B). Preset chromatography gradient methodswere chosen on the basis of compound properties.

Methyl Amine Synthesis: Reductive Amination

0.6 mmol of Reagent A (in case of amine salt, an additional 1.5equivalent amount of DIPEA was added to the reaction mixture) wasdissolved in 3 mL of methanol and the reaction mixture was stirred in avial at r.t. Then 0.6 mmol of Reagent B was added to the stirredsolution. The vial with the reaction mixture was sonicated at 58-60° C.for 60-90 min until a complete dissolution of the reagents. Up to 5 mLof acetonitrile could be added to complete the dissolution of thereagents. The reaction vial was cooled to 0° C. and sodium borohydride(150 mg) was added to the reaction mixture in small portions. Thereaction mixture was stirred in the open vial until sodium borohydridewas dissolved. The reaction vial was sonicated for 2 hrs at r.t.,closed, and allowed to stand overnight at r.t. Then the open reactionvial was sonicated at 50° C. until methanol was nearly completelyevaporated. The reaction mixture was triturated with 5 mL of methanoland stirred until the large part of it was dissolved. The insoluble partlargely consisted of inorganic salts. The product was purified bypassing the methanolic suspension through ionic polymer scavengers. Inthe case of an incomplete dissolution of the product in methanol 5 mL ofdeionized water could be added to the methanolic suspension causingprecipitation of the product and dissolution of the inorganiccontaminants. In the case of an emulsion formation upon addition ofmethanol the reaction mixture was filtered through a smallchromatographic column filled with 8 g of silica gel. The product waseluted with methanol and the solvent removed under reduced pressure toyield the product. Purification of the compounds was performed viapreparative HPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Sulfonamide Synthesis

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), acetonitrile (1 mL), and 0.72 mmol of triethylamine. To thestirred reaction mixture 0.6 mmol of Reagent B was added. The vial wasplaced in a water bath and heated at 100° C. for 2 hrs. 2% Hydrochloricacid (2 mL) was added to the reaction mixture and the vial was shaken.In case a solid precipitate was formed the vial was passed to thefiltration. In case an oily product was formed the vial was sonicated tocause the crystallization. Additional measures to cause thecrystallization of the oily product, e.g., varying the amount of waterand an increase of the sonication time, can be taken. Purification ofthe compounds was performed via preparative HPLC on Agilent 1260Infinity systems equipped with DAD and mass-detectors. Waters SunfireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 PrepGuard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Sulfide Synthesis

A vial was charged with 1.6 mmol of Reagent A, 0.7 ml of DMF and 1.76mmol of thiourea. The reaction mixture was stirred and heated at 100° C.for 2 h. Then it was cooled to rt and 1 mL of 4M KOH solution and 1.6mmol of Reagent B were added. The reaction mixture was sonicated for 24h. Then it was diluted with 3 mL of water and extracted by 3 mL ofCHCl₃. In case of residue formed it was filtered off and purified bypreparative chromatography. The organic layer was washed with water (2*2mL), dried and evaporated. The solid residue was purified by preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Sulfone Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 mL of i-PrOH, 1.6 mmolof Reagent B and 1 mL of 4M KOH solution. The reaction mixture wassonicated at 50-60° C. for 2 h. Then 1 ml of methanol, 0.175 mL ofCH₃COOH, 0.45 mL of 50% H₂O₂ and 0.175 mL of 10% solution of ammoniummolibdate were added. The reaction mixture was sonicated at 70° C. for 5h. Then it was diluted with 3 mL of water and extracted by 3 mL ofCHCl₃. In case of residue formed it was filtered off and purified bypreparative chromatography. The organic layer was washed with 10% NaHCO₃solution (5 mL), dried and evaporated. The solid residue was purified bypreparative HPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Thiazole Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1.5 mL of DMF and 1.6mmol of Reagent B. The reaction mixture was heated at 100° C. for 2hours. After cooling to rt 0.2 ml of DIPEA, 3 mL of water were added andextracted by 3 mL of CHCl₃. Organic layer was washed by water (2*1 mL),dried and evaporated. The solid residue was purified via preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Urea Synthesis

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), 2 mL of acetonitrile and 0.6 mmol of DIPEA. The vial was leftfor 30 minutes, then 0.6 mmol of Reagent B was loaded. A vial was placedin a boiling water bath and heated up for 8 hours, then left for 30minutes to cool down. 1 mL of water was added to the mixture and thevial was sonicated. If the residue has crystallized, the mixture wasstirred until uniform and passed to filtration, otherwise the water wasadded until vial was full and standard workup was used. Filtered solidwas washed with 1 ml of 1:1 isopropyl alcohol-water mixture 2 times.Purification of the compounds was performed via preparative HPLC onAgilent 1260 Infinity systems equipped with DAD and mass-detectors.Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm withSunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used.Solvents used were deionized Water (phase A) and HPLC-grade Methanol(phase B). Preset chromatography gradient methods were chosen on thebasis of compound properties.

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), 2 mL of acetonitrile, 0.9 mmol of DIPEA, and then 0.6 mmol of2,2,2-trifluoroethylchloroformate dropwise. After left for 0.5 hrs, 0.73mmol of Reagent B was added to the mixture. The vial was placed in thewater boiling bath for 8 hrs. After 0.5 hrs cooling down 1 mL of waterwas added and the vial was passed to sonication. The outcome precipitatewas filtered and washed twice with 1 ml of 50% water solution of2-propanol). Purification of the compounds was performed via preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Piperidino-Oxypyrimidine Synthesis

Step A: To a solution of compound 1 (50.0 g, 290 mmol) in chloroform(400 mL) Me₃OBF₄ (34.5 g, 220 mmol) was added. The resulting mixture wasstirred at room temperature for 6 h and then washed with saturatedaqueous solution of K₂CO₃ (2×300 mL). The organic layer was separated,dried over MgSO₄, and evaporated in vacuo. The residue was purified byvacuum distillation (b.p. 78° C. at 1 torr) to give 45.6 g (247 mmol,85%) of compound 2 as a colorless oil.

Step B: Na (12.7 g, 550 mmol) was dissolved in EtOH (200 mL). Compound 3(37.5 g, 238 mmol) was added to the solution and the resulting mixturewas stirred at room temperature for 0.5 h. Then compound 2 (45.6 g, 247mmol) was added, the reaction was refluxed for 4 h, and then evaporatedunder reduced pressure. The residue was dissolved in water andneutralized with 10% HCl. The precipitated solid was filtered andre-crystallized from i-PrOH to yield 40.8 g (179 mmol, 75%) of compound4 as white solid.

Step C: To a suspension of compound 4 (0.020 g, 0.088 mmol) of in dryacetonitrile (2 mL) a solution of 10% HCl in dry dioxane was addeddropwise until pH 3. After standing for 0.5 h the solvents were removedin vacuum to obtain 0.023 g (0.088 mmol, 100%) of target compound 5.

Step D: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile the corresponding acid chloride wasadded (1-3 eq.). The resulting mixture was stirred under reflux for 3hours and then evaporated in vacuo. The residue was purified by HPLC.The obtained product was suspended in dry acetonitrile. 10% HCl in drydioxane was added dropwise until pH 3. After standing for 0.5 h thesolvents were removed under reduced pressure to yield target amides 6.

Step E: To a solution of compound 4 (0.150 g, 0.66 mmol) in acetonitrile[(4-methoxybenzyl)oxy]acetic acid (0.129 g, 0.66 mmol), DIPEA (0.46 mL,2.64 mmol), and DMAP (0.005 g, 0.04 mmol) were added. Then TBTU (0.847g, 2.64 mmol) was added, the resulting mixture was refluxed for 8 hours,and evaporated under reduced pressure. The residue was purified by HPLCto yield the target amide 6.

Step A: To a solution of compound 1 (50.0 g, 290 mmol) in chloroform(400 mL) Me₃OBF₄ (34.5 g, 220 mmol) was added. The resulting mixture wasstirred at room temperature for 6 h and then washed with saturatedaqueous solution of K₂CO₃ (2×300 mL). The organic layer was separated,dried over MgSO₄, and evaporated in vacuo. The residue was purified byvacuum distillation (b.p. 78° C. at 1 torr) to give 45.6 g (247 mmol,85%) of compound 2 as a colorless oil.

Step B: Na (12.7 g, 550 mmol) was dissolved in EtOH (200 mL). Compound 3(37.5 g, 238 mmol) was added to the solution and the resulting mixturewas stirred at room temperature for 0.5 h. Then compound 2 (45.6 g, 247mmol) was added, the reaction was refluxed for 4 h, and then evaporatedunder reduced pressure. The residue was dissolved in water andneutralized with 10% HCl. The precipitated solid was filtered andre-crystallized from i-PrOH to yield 40.8 g (179 mmol, 75%) of compound4 as white solid.

Step C: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile corresponding sulfonyl chloride(0.99 mmol, 1.5 equiv.) was added. The resulting mixture was stirredunder reflux for 2 h and then evaporated in vacuo. The residue waspurified by HPLC to yield the target compounds 5.

Step D: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile the corresponding acid chloride wasadded (1.3-4 eq.). The resulting mixture was stirred under reflux for 3h and then evaporated in vacuo. The residue was purified by HPLC toyield the target amides 6.

Thieno-Oxypyrimidine Synthesis

Step A: To a solution compound 1 (30 g, 0.19 mol) in 300 mL dioxane HClwas added compound 2 (23.85 g, 0.23 mol). The reaction mixture wasstirred at rt overnight, diluted dioxane (300 mL), refluxed for 3 h,cooled and evaporated. The resulting residue was washed by mixtureEtOAc-iPrOH (1:2). The yield was 36 g (0.157 mol, 83%).

Step B: To a solution compound 3 (36 g, 0.157 mol) in 650 mL acetic acidbromine (35 mL) was added at rt. The reaction mixture was refluxed 48 h,cooled, evaporated, diluted with water. The resulting precipitate wasfiltered, washed with water and dried. The yield was 45 g (0.146 mol,93%).

Step C: The mixture compound 4 (35 g, 0.114 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield was 26 g (0.091 mol, 80%).

Step D: Compound 5 (16 g, 0.055 mol) was added to a solution NaOH (21 g,0.525 mol) in 600 mL methanol. The reaction mixture was refluxedovernight, evaporated. The solid residue was washed by water andair-dried. The yield was 12.7 g (0.046 mol, 84%).

Step A: The mixture of compound 1 (50 g, 0.318 mol), compound 2 (54.86g, 0.477 mol) and methylsulfonylmethane (150.6 g, 1.59 mol) was refluxedovernight, cooled and evaporated. The resulting residue was washedmixture EtOAc-iPrOH (1:2). The yield was 41.65 g (0.249 mol, 78%).

Step B: To a solution compound 3 (41.65 g, 0.249 mol) in 700 mL aceticacid was added bromine (42 mL) at rt. The reaction mixture was refluxed48 h, cooled, evaporated, diluted with water. The resulting precipitatewas filtered, washed with water and dried. The yield was 51 g (0.207mol, 83%).

Step C: The mixture of compound 4 (35 g, 0.142 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield was 28 g (0.124 mol, 88%).

Step D: Compound 5 (15 g, 0.067 mol) was added to a solution of NaOH (20g, 0.5 mol) in 600 mL methanol. The reaction mixture was refluxedovernight, evaporated. The solid residue was washed by water andair-dried. The yield was 11.2 g (0.053 mol, 79%).

Amide synthesis from compound 6: The mixture of 1.1 eq of acid 6 and 1eq of corresponding amine was dissolved in 1 ml of HOBt solution in DMF(9.5% wt). Then 1.2 eq of EDC was added and reaction mixture was leftstirring at rt overnight (16-18 h). After completion of the reaction,monitored by LCMS, the reaction mixture was diluted with 4 mL ofdistilled water and left at ultrasonic bath for 30-40 min. The resultingresidue was filtered off, washed by water and dried under high vacuum.If there was no residue formed the aqueous solution was extracted by 4mL of DCM and the organic layer was washed by water (2*4 mL) and thesolvent was removed under reduced pressure. In case of low purity of thefinal compound was subjected to preparative HPLC purification.

Step A: To a solution of compound 1 (50.0 g, 290 mmol) in chloroform(400 mL) Me₃OBF₄ (34.5 g, 220 mmol) was added. The resulting mixture wasstirred at room temperature for 6 h and then washed with saturatedaqueous solution of K₂CO₃ (2×300 mL). The organic layer was separated,dried over MgSO₄, and evaporated in vacuo. The residue was purified byvacuum distillation (b.p. 78° C. at 1 torr) to give 45.6 g (247 mmol,85%) of compound 2 as a colorless oil.

Step B: Na (12.7 g, 550 mmol) was dissolved in EtOH (200 mL). Compound 3(37.5 g, 238 mmol) was added to the solution and the resulting mixturewas stirred at room temperature for 0.5 h. Then compound 2 (45.6 g, 247mmol) was added, the reaction was refluxed for 4 h, and then evaporatedunder reduced pressure. The residue was dissolved in water andneutralized with 10% HCl. The precipitated solid was filtered andre-crystallized from i-PrOH to yield 40.8 g (179 mmol, 75%) of compound4 as a white solid.

Step C: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile corresponding sulfonyl chloride(0.99 mmol, 1.5 equiv.) was added. The resulting mixture was stirredunder reflux for 2 h and then evaporated in vacuo. The residue waspurified by HPLC to yield the target sulfonamides.

Step D: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile the corresponding acid chloride wasadded (1-3 eq.). The resulting mixture was stirred under reflux for 3hours and then evaporated in vacuo. The residue was purified by HPLC.The obtained product was suspended in dry acetonitrile. 10% HCl in drydioxane was added dropwise until pH 3. After standing for 0.5 h thesolvents were removed under reduced pressure to yield the target amides.

Step E: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile the corresponding acid chloride wasadded (1.3-4 eq.). The resulting mixture was stirred under reflux for 3h and then evaporated in vacuo. The residue was purified by HPLC toyield the target amides.

Step A: The mixture of compound 5 (50 g, 0.318 mol), compound 6 (54.86g, 0.477 mol) and methylsulfonylmethane (150.6 g, 1.59 mol) was refluxedovernight, cooled and evaporated. The resulting residue was washed withEtOAc-iPrOH (1:2). The yield of 7 was 41.65 g (0.249 mol, 78%).

Step B: To a solution compound 7 (41.65 g, 0.249 mol) in 700 mL aceticacid was added bromine (42 mL) at rt. The reaction mixture was refluxed48 h, cooled, evaporated, diluted with water. The resulting precipitatewas filtered, washed with water and dried. The yield of 8 was 51 g(0.207 mol, 83%).

Step C: The mixture of compound 8 (35 g, 0.142 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in an autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield of 9 was 28 g (0.124 mol, 88%).

Step D: Compound 9 (15 g, 0.067 mol) was added to a solution of NaOH (20g, 0.5 mol) in 600 mL methanol. The reaction mixture was refluxedovernight and evaporated. The solid residue was washed by water andair-dried. The yield of 10 was 11.2 g (0.053 mol, 79%).

Step E: Amide synthesis from compound 10: 1.1 eq of acid 10 and 1 eq ofcorresponding amine was dissolved in 1 ml of HOBt solution in DMF (9.5%wt). Then 1.2 eq of EDC was added and reaction mixture was left stirringat rt overnight (16-18 h). After completion of the reaction, monitoredby LCMS, the reaction mixture was diluted with 4 mL of distilled waterand left at ultrasonic bath for 30-40 min. The resulting residue wasfiltered off, washed by water and dried under high vacuum to give thetarget amide. If there was no residue formed the aqueous solution wasextracted by 4 mL of DCM and the organic layer was washed by water (2*4mL) and the solvent was removed under reduced pressure to give thetarget amide. In case of low purity of the final compound was subjectedto preparative HPLC purification.

Step A: To a solution compound 5 (30 g, 0.19 mol) in 300 mL dioxane HClwas added compound 11 (23.85 g, 0.23 mol). The reaction mixture wasstirred at rt overnight, diluted dioxane (300 mL), refluxed for 3 h,cooled and evaporated. The resulting residue was washed with EtOAc-iPrOH(1:2). The yield of 12 was 36 g (0.157 mol, 83%).

Step B: To a solution compound 12 (36 g, 0.157 mol) in 650 mL aceticacid, bromine (35 mL) was added at rt. The reaction mixture was refluxed48 h, cooled, evaporated, diluted with water. The resulting precipitatewas filtered, washed with water and dried. The yield of 13 was 45 g(0.146 mol, 93%).

Step C: The mixture of compound 13 (35 g, 0.114 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in an autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield of 14 was 26 g (0.091 mol, 80%).

Step D: Compound 14 (16 g, 0.055 mol) was added to a solution NaOH (21g, 0.525 mol) in 600 mL methanol. The reaction mixture was refluxedovernight, evaporated. The solid residue was washed by water andair-dried. The yield of 15 was 12.7 g (0.046 mol, 84%).

Step E: Amide synthesis from compound 14: 1.1 eq of acid 15 and 1 eq ofcorresponding amine was dissolved in 1 ml of HOBt solution in DMF (9.5%wt). Then 1.2 eq of EDC was added and reaction mixture was left stirringat rt overnight (16-18 h). After completion of the reaction, monitoredby LCMS, the reaction mixture was diluted with 4 mL of distilled waterand left at ultrasonic bath for 30-40 min. The resulting residue wasfiltered off, washed by water and dried under high vacuum to give thetarget amide. If there was no residue formed the aqueous solution wasextracted by 4 mL of DCM and the organic layer was washed by water (2*4mL) and the solvent was removed under reduced pressure to give thetarget amide. In case of low purity of the final compound was subjectedto preparative HPLC purification.

Reactions were conducted on a 100 mg scale, starting with eithercompound 8 (prepared in Step B, Scheme 2) or compound 13 (prepared inStep B, Scheme 3). General procedure: Compound 8 or compound 13 (1 eq.),aryl boronic acid (1.5 eq.), K₂CO₃ (3 eq.) and [1,1′bis(chphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O₂ (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. The organic layer was evaporated and dried in vacuo. The residuewas purified by HPLC to afford the target compounds.

Step A: Compound 16 (10 g, 0.063 mol, 1.0 eq) andpyridine-2-carbonitrile 11 (6.62 g, 0.063 mol, 1.0 eq) were mixed inMeOH (200 mL). The mixture was cooled to 0° C., and sodium methoxide(5.1 g, 0.094 mol, 1.5 eq) was added. The reaction mixture was stirredat reflux for 24 h, concentrated in vacuo, diluted with dichloromethaneand poured into saturated ammonium chloride. The organic layer waswashed with water, saturated sodium chloride, dried over Na₂SO₄,filtered and concentrated in vacuo. The solids were triturated with MTBEto give compound 17 (2.88 g, 20% yield).

Step B: To a solution compound 17 (2 g, 8.72 mmol) in 100 mL aceticacid, bromine (4.1 g, 26.16 mmol, 3.0 eq) was added at rt. The reactionmixture was refluxed 48 h, cooled, evaporated, diluted with water. Theresulting precipitate was filtered, washed with water and dried to give18 as a solid (2.4 g, 90% yield).

Step C: The mixture of compound 18 (2.4 g, 7.84 mmol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in an autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield of 19 was 1.8 g (6.27 mmol, 80% yield).

Step D: The compound 19 (5 g, 0.017 mol, 1 eq.) and phosphoryl chloride(100 mL) were heated at reflux for 24 h. The reaction mixture was thenevaporated to dryness. The crude residue was dissolved in CH₂Cl₂ andwashed carefully with ice-water and 5% NaHCO₃ solution. Organic layerwas dried over Na₂SO₄ and evaporated to dryness giving sufficiently purecompound 20 as a powder (5.05 g, yield 95%).

Step E: General procedure for chlorine displacement. To a stirredsolution of 20 in CHCl₃, was added triethylamine (1.5 eq.) andappropriate amine (1.2 eq) in one portion, and the reaction left to stirat reflux for 4 hours. The reaction mixture was washed with water twiceand evaporated under reduced pressure to give crude product. The crudematerial was purified by column chromatography using CHCl₃: MeCN (1:4)as eluent to afford compounds 21.

Step F: General procedure for ester hydrolysis. Compound 21 was added toa 1M solution of NaOH in methanol. The reaction mixture was heated atreflux overnight and evaporated. The solid residue was dissolved inwater and acidified by 3N HCl to pH ˜4-5. The precipitate being formedwas filtered and washed with water and dried in vacuo to give pure acids22.

Step G: General procedure for amide synthesis. Reactions were conductedon a 100 mg scale. 1.1 eq of acid 22 and 1 eq of corresponding amineR³R⁴NH was dissolved in 1 ml of HOBt solution in DMF (9.5% wt). Then 1.2eq of EDC was added and reaction mixture was left stirring at rtovernight (16-18 h). After completion of the reaction, monitored byLCMS, the reaction mixture was diluted with 4 ml of distilled water andleft at ultrasonic bath for 30-40 min. The resulting residue wasfiltered off, washed by water and dried under high vacuum to give thetarget compounds. If there was no residue formed the aqueous solutionwas extracted by 4 ml of DCM and the organic layer was washed by water(2*4 ml) and the solvent was removed under reduced pressure to give thetarget compounds. In cases of low purity the target compound wassubjected to preparative HPLC purification.

Step A: A mixture of 157.8 g. (1.0 mol) of 2-pyridinecarboxamidinehydrochloride 23, 54.2 g (1.0 mol) of sodium methoxide in 400 ml of drymethanol was stirred for 30 minutes. The sodium chloride was filteredand the filtrate was concentrated to dryness. The residue and 83 g (1.0mole) of 3-methoxyacrylonitrile 24 were heated)(100-160° together for 3hours, at this point the evolution of ethanol had stopped and the melthad started to crystallize. The product 25 was cooled to roomtemperature, suspended in methanol, filtered and dried to obtain 25125.6 g, (73% yield).

Step B: Reactions were conducted on a 100 mg scale. General procedurefor amide synthesis: 1.1 eq of the appropriate acid and 1 eq of 25 wasdissolved in 1 ml of HOBt solution in DMF (9.5% wt). Then 1.2 eq of EDCwas added and reaction mixture was left stirring at rt overnight (16-18h). After completion of the reaction, monitored by LCMS, the reactionmixture was diluted with 4 ml of distilled water and left at ultrasonicbath for 30-40 min. The resulting residue was filtered off, washed bywater and dried under high vacuum to give the target compound. If therewas no residue formed the aqueous solution was extracted by 4 ml of DCMand the organic layer was washed by water (2*4 ml) and the solvent wasremoved under reduced pressure to give the target compound. In case oflow purity of the final compound was subjected to preparative HPLCpurification.

Step A: NaOMe (4.46 g, 82.64 mmol) was added to a solution of diethyl2-methylmalonate 26 (14.34 g, 82.64 mmol) and pyridine-2-carboxamidine23 (10 g, 82.64 mmol) in MeOH (200 ml). The reaction mixture was heatedunder reflux for 40 min resulting in the formation of a precipitate. Thereaction mixture was diluted with MeOH (100 ml) and EtOAc (200 ml) andthe precipitate was triturated and collected by filtration to give 27(11.57 g, 57 mmol, 69% yield).

Step B: Compound 27 was heated at reflux for 24 h in phosphorylchloride. The reaction mixture was then evaporated to dryness. The cruderesidue was dissolved in CH₂Cl₂ and washed carefully with ice-water and5% NaHCO₃ solution. The organic layer was dried over Na₂SO₄ andevaporated to dryness to give compound 28.

Step C: A solution of 28 (2 g, 8.36 mmol) and ammonia in methanol (100mL) was added to a 0.5 L round bottom flask. The solution was stirred at50° C. for 5 h. The reaction mixture was cooled to room temperature. Theprecipitate was filtered, washed with cold methanol (20 mL) and driedunder reduced pressure to give 29 (1.5 g, 81% yield) as a white solid.

Step D: The compound 29 (1.5 g, 6.81 mmol) was suspended in a mixture ofmethanol (10 mL), ethyl acetate (10 mL) and triethylamine (0.948 mL,6.81 mmol). 10% Pd/C was added to the mixture and the resultingsuspension was stirred at room temperature for 2 hours under a hydrogenatmosphere and then filtered. The filtrate was concentrated in vacuo,and purified by silica gel column chromatography to give the titlecompound 30 (0.81 g, 64% yield) as a brown solid.

Step E: Reactions were conducted on a 100 mg scale. 1.1 eq of theappropriate acid and 1 eq of 30 was dissolved in 1 ml of HOBt solutionin DMF (9.5% wt). Then 1.2 eq of EDC was added and reaction mixture wasleft stirring at rt overnight (16-18 h). After completion of thereaction, monitored by LCMS, the reaction mixture was diluted with 4 mlof distilled water and left at ultrasonic bath for 30-40 min. Theresulting residue was filtered off, washed by water and dried under highvacuum to give the target compounds. If there was no residue formed theaqueous solution was extracted by 4 ml of DCM and the organic layer waswashed by water (2*4 ml) and the solvent was removed under reducedpressure to give the target compounds. In cases of low purity, the finalcompound was subjected to preparative HPLC purification.

Step A: The compound 17 (20 g, 0.087 mol, 1 eq.) and phosphoryl chloride(300 mL) were heated at reflux for 24 h. The reaction mixture was thenevaporated to dryness. The crude residue was dissolved in CH₂Cl₂ andwashed carefully with ice-water and 5% NaHCO₃ solution. Organic layerwas dried over Na₂SO₄ and evaporated to dryness giving sufficiently purecompound 31 as yellowish powder (20.5 g, yield 95%).

Step B: Compound 31 (10 g, 0.0405 mol, 1 eq) was stirred in 25% aqueoussolution of ammonia (200 mL) at 100° C. in autoclave for 10 h. Thenreaction mixture was cooled to r.t. and precipitate was filtered, washedwith water and air dried to give compound 32 as white solid (8.77 g, 95%yield).

Step C: Reactions were conducted on a 100 mg scale. 1.1 eq of theappropriate acid and 1 eq of 32 was dissolved in 1 ml of HOBt solutionin DMF (9.5% wt). Then 1.2 eq of EDC was added and reaction mixture wasleft stirring at rt overnight (16-18 h). After completion of thereaction, monitored by LCMS, the reaction mixture was diluted with 4 mlof distilled water and left at ultrasonic bath for 30-40 min. Theresulting residue was filtered off, washed by water and dried under highvacuum to give the target compounds. If there was no residue formed theaqueous solution was extracted by 4 ml of DCM and the organic layer waswashed by water (2*4 ml) and the solvent was removed under reducedpressure to give the target compounds. In case of low purity of thefinal compound was subjected to preparative HPLC purification.

Step A: Compound 33 (20 g, 105.8 mmol, 1 eq.) was suspended in anhydrousTHF (300 mL) and cooled to −100° C. A THF solution of 3M MeMgCl (43 mL,1.2 eq.) was added and the reaction was stirred at ambient temperaturefor 30 min. Solution cooled to −78° C. and ethyl bromoacetate (13 ml,116.4 mmol) was added dropwise and the reaction was allowed to warm toroom temperature. After 18 hours the reaction was quenched with methanoland mixture was concentrated to dryness under reduced pressure. Theresidue was purified by silica gel column chromatography to givecompound 34 (7 g, 25% yield)

Step B: To a solution of 34 (7 g, 26.8 mmol) in THF was added morpholine(7 mL, 80.4 mmol). After 24 hours the reaction was completed. Thereaction mixture was filtered and washed with water to give 35 (6.5 g,78% yield).

Step C: A solution of 2-(tributylstannyl)pyridine 36 (7.82 g, 21.25mmol), compound 35 (6.5 g, 20.85 mmol) and Pd(dppf)₂(5 mol %) in DIVIF(100 mL) was heated at 150° C. for 5 days. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in MTBE (200 mL).The resulting organic solution was washed with water (2×100 mL) andsaturated sodium chloride solution (100 mL). The organic layer wasseparated and dried over Na₂SO₄, filtered through SiO₂ pad, andevaporated to dryness. The residue was purified by column chromatographyaffording compound 37 (1.8 g, 24% yield)

Step A: Compound 39 was prepared analogously to 12 as described inScheme 3, Step A.

Step B: Compound 40 was prepared analogously to 13 as described inScheme 3, Step B.

Step C: Compound 41 was prepared from compound 13, and compound 42 wasprepared from compound 40, using a procedure analogous to the proceduredescribed in Step C of Example 65.

Step D: Compound 43 was prepared from compound 41, and compound 44 wasprepared from compound 42, using a procedure analogous to the proceduredescribed in Step B, Scheme 8 for the preparation of compound 32.

Step F: Compound 45 was prepared from compound 12, prepared as describedin Scheme 3, Step A, and compound 46 was prepared from compound 39,using a procedure analogous to the procedure described in Step C ofExample 65.

Step A: Compound 48 was prepared from compound 47 and compound 11 usinga procedure analogous to the preparation of compound 12 in Step A,Scheme 3.

Step B: A mixture of compound 48 (4 g, 11.26 mmol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (100 ml) was stirredovernight under CO (10 bar) in autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield of 49 was 2.65 g (9.24 mmol, 82% yield).

Step C: Compound 50 was prepared analogously to compound 15 in Step D ofScheme 3 using the general procedure for ester hydrolysis.

Step D: Reactions were conducted on a 100 mg scale. 1.1 eq of acid 50and 1 eq of corresponding amine was dissolved in 1 ml of HOBt solutionin DMF (9.5% wt). Then 1.2 eq of EDC was added and reaction mixture wasleft stirring at rt overnight (16-18 h). After completion of thereaction, monitored by LCMS, the reaction mixture was diluted with 4 mlof distilled water and left at ultrasonic bath for 30-40 min. Theresulting residue was filtered off, washed by water and dried under highvacuum to give the target amides. If there was no residue formed theaqueous solution was extracted by 4 ml of DCM and the organic layer waswashed by water (2*4 ml) and the solvent was removed under reducedpressure to give the target amides. In case of low purity of the finalcompound was subjected to preparative HPLC purification.

Reactions were conducted on a 100 mg scale, starting with compound 13(prepared in Step B, Scheme 3) or compound 40 (prepared in Step B,Scheme 10). General procedure: Compound 13 or compound 40 (1 eq.), theappropriate aryl or heteroaryl boronic acid (1.5 eq.), K₂CO₃ (3 eq.) and[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. The organic layer was evaporated and dried in vacuo. The residuewas purified by HPLC to afford the target compounds.

Step A: Hexamethyldisilazane (1.5 eq) was added dropwise to HOAc (7 mL).The resulting mixture was added to a suspension of malononitrile 52 (2.0eq) and compound 51 (1.0 eq) in HOAc (5 mL). The reaction mixture wasstirred with reflux overnight then, allowed to cool down to RT anddiluted with toluene (30 mL) and water (20 mL). The organic layer wasseparated, washed with water (3*2 mL), dried over Na₂SO₄ andconcentrated under reduced pressure affording compound 53. The scale wascalculated based on a theoretical yield of 2 g of product.

Step B: Sulphur (1.2 eq) was added to a solution of compound 53 (1.0 eq)in THF (20 mL). The resulting mixture was stirred at 50° C. for 30 minand then NaHCO₃ (1.0 eq) was added. Then, the reaction mixture wasstirred at 50° C. overnight and diluted with EtOAc. The organic phasewas dried with Na₂SO₄ and evaporated in vacuo to obtain compound 54. Thescale was calculated based on a theoretical yield of 1.4 g of product.

Step C: The compound 54 (1.0 eq) and 80% H₂SO₄(10 mL) were stirred at RTfor 18 h. After completion (monitored by LCMS), the reaction mixture waspoured in ice and aqueous ammonia (5 mL) was added. The precipitateformed was filtered off, washed with water and air-dried. The scale wascalculated based on a theoretical yield of 0.5 g of product.

Step D: Lithium 1-methyl-1H-imidazole-2-carboxylate 56 (1.3 eq),triethylamine (1.4 eq) and 1-methyl-1H-imidazole (2.5 eq) were dissolvedin CH₂Cl₂ (15 mL). The resulting mixture was cooled to 0° C. andmethanesulfonyl chloride (1.2 eq) was added dropwise. Then, theresulting suspension was stirred for 30 min and compound 55 (1.0 eq) wasadded in one portion. The reaction mixture was stirred overnight andevaporated in vacuo. The residue was dissolved in DMSO and potassiumtert-butoxide (2.0 eq) was added. The resulting suspension was stirredovernight at 80° C. and HOAc (5 mL) was added. The resulting precipitatewas filtered off, washed with water and dried to give 57. The scale wascalculated based on a theoretical yield of 300 mg of product.

Step E: The compound 57 (1.0 eq.) and phosphoryl chloride (7 mL) werestirred at 90° c. for 18 h. The reaction mixture was poured into ice andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andthe solvent was removed under reduced pressure to give the compound 58.The scale was calculated based on a theoretical yield of 170 mg ofproduct.

Step F: To a solution of compound 58 (1.0 eq) in DMSO (3 mL), theappropriate amine (1.0 eq) and DIPEA (1.3 eq) were added. The resultingmixture was stirred overnight at 60° C. Then, the reaction suspensionwas poured into water and extracted with EtOAc. The solvent wasevaporated and the residue was purified by HPLC to obtain the targetcompounds. The scale was calculated based on a theoretical yield of 100mg of final product.

Step A: Hexamethyldisilazane (1.5 eq) was added dropwise to HOAc (7 mL).The resulting mixture was added to a suspension of malononitrile 52 (2.0eq) and compound 59 (1.0 eq) in HOAc (5 mL). The reaction mixture wasstirred with reflux overnight then, allowed to cool down to RT anddiluted with toluene (30 mL) and water (20 mL). The organic layer wasseparated, washed with water (3*2 mL), dried over Na₂SO₄ andconcentrated under reduced pressure affording compound 60. The scale wascalculated based on a theoretical yield of 2 g of product.

Step B: Sulphur (1.2 eq) was added to a solution of compound 60 (1.0 eq)in THF (20 mL). The resulting mixture was stirred at 50° C. for 30 minand then NaHCO₃ (1.0 eq) was added. Then, the reaction mixture wasstirred at 50° C. overnight and diluted with EtOAc. The organic phasewas dried with Na₂SO₄ and evaporated in vacuo to obtain compound 61. Thescale was calculated based on a theoretical yield of 0.5 g of product.

Step C when R=4-methoxyphenyl: The compound 61 (1.0 eq) andpolyphosphoric acid (10 mL) were stirred at 80° C. for 18 h. Aftercompletion of the reaction (monitored by LCMS) the reaction mixture waspoured in ice and sodium hydroxide (5 mL) was added. The resultingprecipitate was filtered off, washed with water and dried. The yield was61% The scale was calculated based on a theoretical yield of 0.5 g ofproduct.

Step C when R=2-chlorophenyl: The compound 61 (1.0 eq) and 80% H₂SO₄ (10mL) were stirred at RT for 18 h. After completion (monitored by LCMS),the reaction mixture was poured in ice and aqueous ammonia (5 mL) wasadded. The precipitate formed was filtered off, washed with water andair-dried. The scale was calculated based on a theoretical yield of 0.5g of product.

Step C when R=4-pyridinyl or 2-pyridinyl: The compound 61 (1.0 eq) and80% H₂SO₄(10 mL) were stirred at 80° C. for 24 h. After completion ofthe reaction (monitored by LCMS) the reaction mixture was poured in iceand ammonia (5 mL) was added. The resulting precipitate was filteredoff, washed with water and air-dried. The yield was 72%. The scale wascalculated based on a theoretical yield of 0.5 g of product.

Step D: Lithium 1-methyl-1H-imidazole-2-carboxylate 56 (1.3 eq),triethylamine (1.4 eq) and 1-methyl-1H-imidazole (2.5 eq) were dissolvedin CH₂Cl₂ (15 mL). The resulting mixture was cooled to 0° C. andmethanesulfonyl chloride (1.2 eq) was added dropwise. Then, theresulting suspension was stirred for 30 min and compound 62 (1.0 eq) wasadded in one portion. The reaction mixture was stirred overnight andevaporated in vacuo. The residue was dissolved in DMSO and potassiumtert-butoxide (2.0 eq) was added. The resulting suspension was stirredovernight at 80° C. and HOAc (5 mL) was added. The resulting precipitatewas filtered off, washed with water and dried to give 63. The scale wascalculated based on a theoretical yield of 300 mg of product.

Step E: The compound 63 (1.0 eq.) and phosphoryl chloride (7 mL) werestirred at 90° c. for 18 h. The reaction mixture was poured into ice andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andthe solvent was removed under reduced pressure to give the compound 64.The scale was calculated based on a theoretical yield of 180 mg ofproduct.

Step F: To a solution of compound 64 (1.0 eq) in DMSO (3 mL),2-methoxyethanamine (1.0 eq) and DIPEA (1.3 eq) were added. Theresulting mixture was stirred overnight at 60° C. Then, the reactionsuspension was poured into water and extracted with EtOAc. The solventwas evaporated and the residue was purified by HPLC to obtain the targetcompounds. The scale was calculated based on a theoretical yield of 100mg of final product.

Step A: Hexamethyldisilazane (1.5 eq) was added dropwise to HOAc (7 mL).The resulting mixture was added to a suspension of malononitrile 52 (2.0eq) and compound 65 (1.0 eq) in HOAc (5 mL). The reaction mixture wasstirred with reflux overnight then, allowed to cool down to RT anddiluted with toluene (30 mL) and water (20 mL). The organic layer wasseparated, washed with water (3*2 mL), dried over Na₂SO₄ andconcentrated under reduced pressure affording compound 66. The scale wascalculated based on a theoretical yield of 2 g of product.

Step B: Sulphur (1.2 eq) was added to a solution of compound 66 (1.0 eq)in THF (20 mL). The resulting mixture was stirred at 50° C. for 30 minand then NaHCO₃ (1.0 eq) was added. Then, the reaction mixture wasstirred at 50° C. overnight and diluted with EtOAc. The organic phasewas dried with Na₂SO₄ and evaporated in vacuo to obtain compound 67. Thescale was calculated based on a theoretical yield of 1.5 g of product.

Step C when R=3-methoxyphenyl: The compound 67 (1.0 eq) andpolyphosphoric acid (10 mL) were stirred at 80° C. for 18 h. Aftercompletion of the reaction (monitored by LCMS) the reaction mixture waspoured in ice and sodium hydroxide (5 mL) was added. The resultingprecipitate was filtered off, washed with water and dried to give 68.The scale was calculated based on a theoretical yield of 0.5 g ofproduct.

Step C when R=2-chlorophenyl: The compound 67 (1.0 eq) and 80% H₂SO₄(10mL) were stirred at RT for 18 h. After completion (monitored by LCMS),the reaction mixture was poured in ice and aqueous ammonia (5 mL) wasadded. The precipitate formed was filtered off, washed with water andair-dried to give 68. The scale was calculated based on a theoreticalyield of 0.5 g of product.

Step D: Lithium 1-methyl-1H-imidazole-2-carboxylate 56 (1.3 eq),triethylamine (1.4 eq) and 1-methyl-1H-imidazole (2.5 eq) were dissolvedin CH₂Cl₂ (15 mL). The resulting mixture was cooled to 0° C. andmethanesulfonyl chloride (1.2 eq) was added dropwise. Then, theresulting suspension was stirred for 30 min and compound 68 (1.0 eq) wasadded in one portion. The reaction mixture was stirred overnight andevaporated in vacuo. The residue was dissolved in DMSO and potassiumtert-butoxide (2.0 eq) was added. The resulting suspension was stirredovernight at 80° C. and HOAc (5 mL) was added. The resulting precipitatewas filtered off, washed with water and dried to give 69. The scale wascalculated based on a theoretical yield of 300 mg of product.

Step E: The compound 69 (1.0 eq.) and phosphoryl chloride (7 mL) werestirred at 90° c. for 18 h. The reaction mixture was poured into ice andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andthe solvent was removed under reduced pressure to give the compound 70.The scale was calculated based on a theoretical yield of 170 mg ofproduct.

Step F: To a solution of compound 70 (1.0 eq) in DMSO (3 mL),2-methoxyethanamine (1.0 eq) and DIPEA (1.3 eq) were added. Theresulting mixture was stirred overnight at 60° C. Then, the reactionsuspension was poured into water and extracted with EtOAc. The solventwas evaporated and the residue was purified by HPLC to obtain the targetcompounds. The scale was calculated based on a theoretical yield of 100mg of final product.

Step A: Hexamethyldisilazane (1.5 eq) was added dropwise to HOAc (7 mL).The resulting mixture was added to a suspension of malononitrile 52 (2.0eq) and compound 51 (1.0 eq) in HOAc (5 mL). The reaction mixture wasstirred with reflux overnight then, allowed to cool down to RT anddiluted with toluene (30 mL) and water (20 mL). The organic layer wasseparated, washed with water (3*2 mL), dried over Na₂SO₄ andconcentrated under reduced pressure affording compound 53. The scale wascalculated based on a theoretical yield of 2 g of product.

Step B: Sulphur (1.2 eq) was added to a solution of compound 53 (1.0 eq)in THF (20 mL). The resulting mixture was stirred at 50° C. for 30 minand then NaHCO₃ (1.0 eq) was added. Then, the reaction mixture wasstirred at 50° C. overnight and diluted with EtOAc. The organic phasewas dried with Na₂SO₄ and evaporated in vacuo to obtain compound 54. Thescale was calculated based on a theoretical yield of 1.5 g of product.

Step C: The compound 54 (1.0 eq) and 80% H₂SO₄(10 mL) were stirred at RTfor 18 h. After completion (monitored by LCMS), the reaction mixture waspoured in ice and aqueous ammonia (5 mL) was added. The precipitateformed was filtered off, washed with water and air-dried to give 55. Thescale was calculated based on a theoretical yield of 0.5 g of product.

Step D: To a solution of compound 55 (1.0 eq) in DMF (5 mL), theappropriate aldehyde (1.5 eq) was added. The resulting mixture wasstirred at 90° C. overnight. Then, the mixture was diluted with water (5mL) and the product was extracted with CH₂Cl₂ (3.2 mL). The organicphase was dried with Na₂SO₄ and evaporated in vacuo affording crudeproduct. The residue was recrystallized from MeOH to obtain pure product71 (51% yield). The scale was calculated based on a theoretical yield of300 mg of product.

Step E: The compound 71 (1.0 eq.) and phosphoryl chloride (7 mL) werestirred at 90° c. for 18 h. The reaction mixture was poured into ice andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andthe solvent was removed under reduced pressure to give the compound 72.The scale was calculated based on a theoretical yield of 160 mg ofproduct.

Step F: To a solution of compound 72 (1.0 eq) in DMSO (3 mL),2-methoxyethanamine (1.0 eq) and DIPEA (1.3 eq) were added. Theresulting mixture was stirred overnight at 60° C. Then, the reactionsuspension was poured into water and extracted with EtOAc. The solventwas evaporated and the residue was purified by HPLC to obtain the targetcompounds. The scale was calculated based on a theoretical yield of 100mg of final product.

Step A: To a solution of compound 73 (1.0 eq) in HOAc (15.0 mL) wasadded Br2 (3.0 eq). The reaction was heated to 60° C. and allowed tostir approximately 45 minutes. The excess Br2 was neutralized withexcess of Na₂S203, and the crude product was extracted (3.25 mL) of DCM.The combined organic layers were dried over MgSO₄ and concentrated invacuo, affording crude compound 74 as a light yellow solid. The productswere used in the next step without purification. The scale of thereaction was calculated based on a theoretical yield of 1 g of 74.

Step B: Compound 74 (1.0 eq), the corresponding boronic acid (1.1 eq),Pd(dppf)Cl₂*CH₂Cl₂ (0.02 eq) and potassium carbonate (2.0 eq) in dioxane(2 mL) and water (1 mL) was heated at 90° C. overnight under Aratmosphere. After cooling, the mixture was purified by flashchromatography on silica gel using 1:4 ethyl acetate/hexanes to give thetarget compounds 75. The scale of the reaction was calculated based on atheoretical yield of 0.5 g of 75.

Step C: Compound 75 (1.0 eq), 1-methyl-2-cyanoimidazole (1.1 eq) andsodium tert-butoxide (2.0 eq) in dry THF (2 ml) was heated at reflux for12 hours. After cooling, the mixture was poured into water (2 ml). Theformed precipitated solid was collected and purified by HPLC to give thetarget compounds 76. The scale of the reaction was calculated based on atheoretical yield of 200 mg of 76.

Step A—Step B: Into a 500 mL flask were charged 13 (1 g, 3.25 mmol, 1eq.),[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.132 g, 0.16 mmol, 0.05 eq.), cuprous iodide (0.061 g, 0.32mmol, 0.1 eq.), and THF (50 mL). The resulting mixture was degassed withalternating vacuum/nitrogen purges. The filtered organozinc reagent 78(9.75 mmol, prepared as described in J. Org. Chem. 2004, 69, 5120-5123from iodide 77) was then added. The mixture was degassed one more timeand then heated at reflux for 24 h. The reaction mixture was then cooledto 20° C. and treated with MTBE (methyl tert-butyl ether, 130 mL) and 1N ammonium chloride (130 mL). The mixture was stirred at 20-30° C. for30 min and then filtered. The lower aqueous layer was drawn off, and theremaining organic layer was treated with saturated aqueous NH₄Cl (50 mL)and stirred for 30 min. After settling, the lower aqueous layer wasremoved and the organic layer was collected. The resulting organicsolution was then filtered through a small pad of SiO₂. The SiO₂ pad waswashed with MTBE (25 mL). The solvent was evaporated, and the residuewas purified by HPLC to give the products 79.

Into a 500 mL flask were charged 13 (1 g, 3.25 mmol, 1 eq.),[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.132 g, 0.16 mmol, 0.05 eq.), cuprous iodide (0.061 g, 0.32mmol, 0.1 eq.), and THF (50 mL). The resulting mixture was degassed withalternating vacuum/nitrogen purges. The filtered organozinc reagent 81(9.75 mmol, prepared as described in J. Org. Chem. 2004, 69, 5120-5123from 80) was then added. The mixture was degassed one more time and thenheated at reflux for 24 h. The reaction mixture was then cooled to 20°C. and treated with MTBE (methyl tert-butyl ether, 130 mL) and 1 Nammonium chloride (130 mL). The mixture was stirred at 20-30° C. for 30min and then filtered. The lower aqueous layer was drawn off, and theremaining organic layer was treated with saturated aqueous NH₄Cl (50 mL)and stirred for 30 min. After settling, the lower aqueous layer wasremoved and the organic layer was collected. The resulting organicsolution was then filtered through a small pad of SiO₂. The SiO₂ pad waswashed with MTBE (25 mL). The solvent was evaporated, and the residuewas purified by HPLC to give the target compounds.

Purification and Analytical Procedures:

Purification was performed using HPLC (H₂O-MeOH; Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm) The material was dissolved in 0.7mL DMSO. Flow:30 mL/min. Purity of the obtained fractions was checkedvia the analytical LCMS. Spectra were recorded for each fraction as itwas obtained straight after chromatography in the solution form. Thesolvent was evaporated under the N₂ flow upon heating to 80° C. On thebasis of post-chromatography LCMS analysis fractions were united. Solidfractions were dissolved in 0.5 mL MeOH and transferred into apre-weighted marked vials. Obtained solutions were again evaporatedunder the N₂ flow upon heating to 80° C. After drying, products werefinally characterized by LCMS and ¹H NMR.

NMR Instrument specifications: Bruker AVANCE DRX 500, Varian UNITYplus400.

LC/MS Instrument specifications: Agilent 1100 Series LC/MSD system withDAD\ELSD and Agilent LC\MSD VL (G1956A), SL (G1956B) mass-spectrometer.Agilent 1200 Series LC/MSD system with DAD\ELSD and Agilent LC\MSD SL(G6130A), SL (G6140A) mass-spectrometer. All the LC/MS data wereobtained using positive/negative mode switching. Column Zorbax SB-C181.8 μm 4.6×15 mm Rapid Resolution cartridge (PN 821975-932) Mobile phaseA—acetonitrile, 0.1% formic acid, B—water (0.1% formic acid) Flow rate 3ml/min Gradient 0 min—100% B, 0.01 min—100% B, 1.5 min—0% B, 1.8 min—0%B, 1.81 min—100% B. Injection volume 1 μl. Ionization mode atmosphericpressure chemical ionization (APCI). Scan range m/z 80-1000

TABLE 3 Mass Spectral Data M + H M + H Compound MW (calculated)(observed)

265 229.1 229.2

399 363.1 363.0

406 407.2 407.2

427 391.2 391.2

420 384.2 384.0

411 375.2 375.1

435 399.2 399.2

328 329.2 329.2

323 324.1 324.2

376 377.1 377.2

396 397.1 397.2

368 369.1 369.2

376 377.2 377.2

437 437.2 437.1

332 333.1 333.2

333 334.1 334.0

375 376.2 376.2

246 245.9 246.0

292 293.1 293.0

322 323.1 323.0

350 351.1 351.0

350 351.2 351.2

363 364.1 364.2

361 362.1 362.2

355 356.1 356.1

356 357.1 357  

308 309.1 309.0

344 308.1 308.2

365 366.1 366.0

326 327.1 327.0

342 343.1 343.2

329 330.1 330.2

315 316.1 316.0

340 341.1 341.2

400 401.1 401.0

308 307.9 308.0

354 355.1 355.2

384 385.1 385.0

413 413.2 413.2

413 413.2 413.2

426 426.2 426.0

423 424.2 424.2

417 418.1 418.2

418 419.1 419.0

417 418.1 418.2

370 371.1 371.0

442 370.1 370.2

427 428.1 428.0

388 389.1 389.2

404 405.1 405.0

391 392.1 392.2

377 378.1 378.2

402 403.1 403.0

463 463.2 463.2

243 244.3 244.0

278 278.0 278.0

305 306.1 306.0

340 340.0 339.9

289 290.1 290.2

290 291.1 291.0

351 352.1 352.2

315 316.1 316.0

377 377.0 377.0

298 299.1 299.1

308 307.9 308.0

229 230.0 230.0

312 313.1 313.0

356 356.2 356.2

333 333.1 333.0

259 260.0 260.2

314 315.1 315.1

369 370.2 370.2

385 313.1 313.2

448 448.2 448.0

448 448.2 448.2

448 448.2 448.2

433 434.1 434.0

433 434.1 434.0

433 434.1 434.0

452 452.1 452.0

452 452.1 452.1

452 452.1 452.0

435 436.1 436.0

442 443.1 443.0

432 432.2 432.2

466 466.1 466.0

462 462.2 462.2

448 448.2 448.2

492 492.2 492.2

446 446.2 446.2

448 449.1 449.0

453 453.1 453.0

436 437.1 437.0

436 437.1 437.0

434 435.1 435.0

425 426.1 426.0

417 418.1 418.2

452 452.1 452.0

435 436.1 436.0

490 490.2 490.2

441 441.2 441.2

335 336.2 336.2

366 367.1 367.0

338 338.0 338.0

436 437.1 437.2

447 447.2 447.1

477 477.2 477.1

491 491.2 491.1

477 477.2 477.1

478 478.2 478.0

453 453.1 453.1

471 471.2 471.1

343 344.2 344.3

399 400.1 400.2

435 436.1 436.0

435 436.1 436.0

442 443.1 443.1

442 443.1 443.1

478 478.2 478.0

508 508.2 508.2

478 478.2 478.2

453 454.1 454.2

432 432.2 432.2

432 432.2 432.2

462 462.2 462.2

448 448.2 448.0

482 482.1 482.1

418 419.1 419.0

448 449.1 449.2

448 449.1 449.1

453 453.1 453.2

453 453.1 453.2

432 433.1 433.2

448 448.2 448.0

448 448.2 448.0

448 448.2 448.0

432 432.1 432.1

435 436.1 436.0

421 422.1 422.1

432 432.2 432.1

447 447.2 447.2

477 477.2 477.2

491 491.2 491.2

284 285.0 285.0

463 463.2 463.2

448 448.2 448.2

478 478.2 478.2

437 438.1 438.2

471 471.2 471.1

485 485.2 485.2

428 428.2 428.2

442 442.2 442.2

477 477.1 477.2

523 523.2 523.2

474 474.2 474.2

329 330.1 330.1

346 347.2 347.2

345 346.1 346.2

343 344.2 344.1

385 386.1 386.0

401 402.1 402.2

294 294.0 294.0

192 156.1 156.2

464 464.1 464.0

468 468.1 468.2

446 446.2 446.2

442 442.2 442.2

452 452.1 452.2

435 436.1 436.0

433 434.1 434.0

463 463.2 463.2

464 464.2 464.2

462 462.1 462.1

510 510.2 510.2

351 352.1 352.2

329 330.1 330.0

359 360.2 360.0

351 352.1 352.2

371 372.1 372.0

402 403.1 403.0

323 324.1 324.0

464 464.1 464.2

304 305.1 305.0

287 288.0 288.0

477 478.2 478.2

339 340.1 340.2

476 476.2 476.2

369 370.2 370.2

377 378.1 378.0

377 378.1 378.0

462 462.2 462.2

450 450.2 450.0

450 450.2 450.0

228 229.1 229.0

339 339.1 339.2

242 243.1 243.0

318 319.1 319.2

429 430.1 430.2

403 404.1 404.1

418 419.1 419.0

417 418.1 418.2

418 419.1 419.0

377 378.1 378.2

403 404.2 404.0

380 381.1 381.0

367 368.1 368.1

361 362.2 362.2

374 374.0 374.0

349 350.1 350.1

273 274.0 274.0

321 285.1 285.1

335 299.1 299.1

525 525.1 525.2

512 512.1 512  

355 356.2 356.0

355 356.1 356.3

393 394.1 394.0

407 408.1 408.0

304 305.1 305.2

389 390.1 390.0

360 361.1 361.0

391 392.1 392.2

389 390.1 390.0

453 453.1 453.0

359 360.1 360.0

403 404.2 404.2

405 406.1 406.2

323 324.1 324.1

363 364.1 364.2

335 336.1 336.0

341 342.1 342.0

335 336.1 336.2

373 374.1 374.2

353 354.1 354.0

311 312.0 312.0

389 390.1 390.2

378 379.1 379.2

385 386.1 386.2

349 350.1 350.2

381 382.1 382.0

349 350.1 350.1

404 405.2 405.2

355 356.1 356.2

404 405.1 405.0

376 377.1 377.0

375 376.1 376.0

403 404.2 404.2

320 321.1 321.1

350 351.1 351.2

352 [M − 1] 351.1 [M − 1] 351.0

362 363.1 363.0

307 307.0 307.0

321 321.0 321.0

307 307.0 307.0

286 287.1 287.0

468 307.1 307.0

478 478.2 478.2

464 464.1 464.2

477 477.2 477.2

341 342.1 342.2

380 381.1 381.2

361 362.1 362.2

337 338.1 338.1

372 373.1 373.0

319 320.1 320.0

287 288.0 288.1

356 357.1 357.0

374 374.0 374.0

324 325.1 325.2

391 392.1 392.0

374 375.1 375.2

320 321.1 321.2

320 321.1 321.0

203 204.1 204.2

232 196.1 196.2

311 312.1 312.0

299 300.1 300.0

243 244.1 244.2

301 302.1 302.0

322 322.0 322.0

287 288.0 288.0

301 302.1 302.0

307 271.1 271.0

320 284.1 284.1

325 326.2 326.2

297 298.1 298.0

231 232.1 232.2

287 288.0 288.0

432 432.2 432.2

321 322.2 322.0

300 301.1 301.0

399 327.1 327.0

308 272.1 272.0

399 327.1 327.0

283 284.1 284.0

246 210.1 210.2

220 184.1 184.2

392 393.2 393.0

391 392.1 392.0

285 286.1 286.0

297 298.1 298.0

206 207.1 207.0

320 321.1 321.0

322 323.1 323.1

300 301.1 301.0

448 448.2 448.0

351 352.1 352.2

406 407.2 407.2

330 331.1 331.0

307 308.1 308.0

323 324.1 324.0

351 352.1 352.2

356 357.1 357.0

432 432.2 432.2

446 446.2 446.0

462 462.2 462.0

348 311.1 312.0

206 207.1 207.2

394 322.1 322.0

354 354.0 354.0

192 193.1 193.2

409 410.1 410.0

269 270.1 270.0

371 299.1 299.0

410 411.1 411.1

410 411.1 411.0

322 322.0 321.9

424 425.1 425.2

424 425.1 425.2

452 452.1 452.0

385 313.1 313.2

361 362.1 362.0

458 386.1 386.2

486 486.2 486.2

443 443.2 443.2

399 400.1 400.2

542 542.2 542.3

482 482.1 482.2

411 412.2 412.0

442 442.2 442.2

384 385.1 385.0

514 514.2 514.2

423 424.2 424.2

366 367.1 367.1

380 381.1 381.2

454 454.2 454.2

369 370.1 370.0

356 357.1 357.0

383 384.1 384.2

366 367.1 367.0

393 394.1 394.2

247 248.1 247.9

382 383.1 383.2

385 386.1 386.2

488 488.2 488.2

412 413.2 413.2

377 378.1 378.0

384 384.0 384.0

364 364.0 364.0

319 320.1 320.0

340 340.0 340.0

363 364.1 364.0

349 350.1 350.1

381 382.1 382.0

319 320.1 320.0

306 307.1 307.0

305 306.1 306.0

335 336.1 336.0

384 384.0 384.0

363 364.1 364.0

456 456.2 456.2

470 470.2 470.2

496 410.2 calculated [M − 85.0] 410.2

442 442.2 422.2

456 456.2 456.2

468 468.2 468.2

457 457.2 457.0

484 484.3 484.0

440 440.2 440.2

456 456.2 456.2

468 468.2 468.2

456 456.2 456.2

442 442.2 442.2

442 442.2 442.0

476 476.2 476.2

476 476.2 476.2

443 443.2 443.2

442 442.2 442.2

379 380.2 380.2

379 380.2 380.2

472 472.2 472.2

458 458.2 458.2

384 384.1 385.2

472 472.2 472.2

450 450.2 450.2

454 454.2 454.2

452 453.1 453.0

415 416.1 416.0

322 323.1 323.1

419 419.1 419.0

443 443.2 443.2

472 472.2 472.2

376 377.1 377.0

390 391.1 391.0

395 396.2 396.2

353 354.4 need

357 357.1 357.0

392 393.1 393.0

376 377.1 377.0

381 382.1 382.2

392 393.1 393.0

374 375.1 375.0

374 375.1 375.0

384 385.1 385.0

398 399.1 399.1

460 461.2 461.1

381 382.1 382.2

339 340.1 340.0

308 309.1 309.0

342 343.0 343.0

344 345.1 345.0

342 343.0 343.0

380 383.1 381.2

364 365.1 365.2

440 440.2 440.2

358 359.1 359.2

443 443.2 443.2

6.6. Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein and apharmaceutically acceptable carrier, diluent or excipient.

The compounds can be formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor ophthalmic or parenteral administration, as well as transdermalpatch preparation and dry powder inhalers. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art (see, e.g., AnselIntroduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable salts is (are) mixed with a suitablepharmaceutical carrier or vehicle. In certain embodiments, theconcentrations of the compounds in the compositions are effective fordelivery of an amount, upon administration, that treats, prevents, orameliorates one or more of the symptoms and/or progression of a diseaseor disorder disclosed herein.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as known in the art. Briefly,liposomes such as multilamellar vesicles (MLV's) may be formed by dryingdown egg phosphatidyl choline and brain phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline lacking divalent cations (PBS) isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the subject treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand then extrapolated therefrom for dosages for humans. In someembodiments, the active compound is administered in a method to achievea therapeutically effective concentration of the drug. In someembodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen JT, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389/fonc.2014.00105) isused to determine the therapeutic concentration and safety profile ofthe active compound in specific subjects or subject populations.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, tissue distribution, inactivation andexcretion rates of the active compound, the physicochemicalcharacteristics of the compound, the dosage schedule, and amountadministered as well as other factors known to those of skill in theart. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of a disease or disorderdisclosed herein.

In certain embodiments, a therapeutically effective dosage shouldproduce a serum concentration of active ingredient of from about 0.1ng/mL to about 50-100 μg/mL. In one embodiment, the pharmaceuticalcompositions provide a dosage of from about 0.001 mg to about 2000 mg ofcompound per kilogram of body weight per day. Pharmaceutical dosage unitforms are prepared to provide from about 1 mg to about 1000 mg and incertain embodiments, from about 10 to about 500 mg of the essentialactive ingredient or a combination of essential ingredients per dosageunit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable salts thereofare mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating, retardingprogression, or preventing. The concentration of active compound in thecomposition will depend on absorption, tissue distribution,inactivation, excretion rates of the active compound, the dosageschedule, amount administered, particular formulation as well as otherfactors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including but not limited to oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, intrathecal, mucosal,dermal, transdermal, buccal, rectal, topical, local, nasal orinhalation. For oral administration, capsules and tablets can beformulated. The compositions are in liquid, semi-liquid or solid formand are formulated in a manner suitable for each route ofadministration.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol, dimethylacetamide or other synthetic solvent; antimicrobial agents, such asbenzyl alcohol and methyl parabens; antioxidants, such as ascorbic acidand sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, pens, disposable syringes or single or multiple dose vialsmade of glass, plastic or other suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablesalts thereof. The pharmaceutically therapeutically active compounds andsalts thereof are formulated and administered in unit dosage forms ormultiple dosage forms. Unit dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired pharmaceutical carrier, vehicle or diluent. Examples of unitdose forms include ampules and syringes and individually packagedtablets or capsules. Unit dose forms may be administered in fractions ormultiples thereof. A multiple dose form is a plurality of identical unitdosage forms packaged in a single container to be administered insegregated unit dose form. Examples of multiple dose forms includevials, bottles of tablets or capsules or bottles of pints or gallons.Hence, multiple dose form is a multiple of unit doses which are notsegregated in packaging.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the compound provided herein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices includeiontophoresis patches, polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides,copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate), andpoly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinylacetate and lactic acid-glycolic acid enable release of molecules forover 100 days, certain hydrogels release proteins for shorter timeperiods. When encapsulated compound remain in the body for a long time,they may denature or aggregate as a result of exposure to moisture at37° C., resulting in a loss of biological activity and possible changesin their structure. Rational strategies can be devised for stabilizationdepending on the mechanism of action involved. For example, if theaggregation mechanism is discovered to be intermolecular S—S bondformation through thio-disulfide interchange, stabilization may beachieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non toxic carrier may beprepared. For oral administration, a pharmaceutically acceptable nontoxic composition is formed by the incorporation of any of the normallyemployed excipients, such as, for example pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain about 0.001% 100% activeingredient, in certain embodiments, about 0.1 85% or about 75-95%.

The active compounds or pharmaceutically acceptable salts may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings.

The compositions may include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable salts thereof as described herein, may alsobe advantageously administered for therapeutic or prophylactic purposestogether with another pharmacological agent known in the general art tobe of value in treating one or more of the diseases or medicalconditions referred to hereinabove, such as diseases related tooxidative stress. It is to be understood that such combination therapyconstitutes a further aspect of the compositions and methods oftreatment provided herein.

Lactose-free compositions provided herein can contain excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions contain an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose-free dosage forms contain an activeingredient, microcrystalline cellulose, pre-gelatinized starch andmagnesium stearate.

Further encompassed are anhydrous pharmaceutical compositions and dosageforms containing a compound provided herein. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are anhydrous ifsubstantial contact with moisture and/or humidity during manufacturing,packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are packaged using materials known to prevent exposure towater such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs and strip packs.

Oral Dosage Forms

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric coated, sugar coated or film coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such ascapsules or tablets. The tablets, pills, capsules, troches and the likecan contain any of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable salt thereof asdescribed herein. Higher concentrations, up to about 98% by weight ofthe active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric coated tablets, because of theenteric coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted from noneffervescent granules and effervescent preparations reconstituted fromeffervescent granules. Aqueous solutions include, for example, elixirsand syrups. Emulsions are either oil in-water or water in oil. In someembodiments, the suspension is a suspension of microparticles ornanoparticles. In some embodiments, the emulsion is an emulsion ofmicroparticles or nanoparticles.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used in noneffervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is encapsulated ina gelatin capsule. Such solutions, and the preparation and encapsulationthereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. For a liquid dosage form, the solution, e.g., for example, ina polyethylene glycol, may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be easilymeasured for administration.

Alternatively, liquid or semi solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include, but are not limited to, those containing acompound provided herein, a dialkylated mono- or poly-alkylene glycol,including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme,tetraglyme, polyethylene glycol-350-dimethyl ether, polyethyleneglycol-550-dimethyl ether, polyethylene glycol-750-dimethyl etherwherein 350, 550 and 750 refer to the approximate average molecularweight of the polyethylene glycol, and one or more antioxidants, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. In someembodiments, the suspension is a suspension of microparticles ornanoparticles. In some embodiments, the emulsion is an emulsion ofmicroparticles or nanoparticles. Suitable excipients are, for example,water, saline, dextrose, glycerol or ethanol. In addition, if desired,the pharmaceutical compositions to be administered may also containminor amounts of non toxic auxiliary substances such as wetting oremulsifying agents, pH buffering agents, stabilizers, solubilityenhancers, and other such agents, such as for example, sodium acetate,sorbitan monolaurate, triethanolamine oleate and cyclodextrins.Implantation of a slow release or sustained release system, such that aconstant level of dosage is maintained is also contemplated herein.Briefly, a compound provided herein is dispersed in a solid innermatrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticizedor unplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propyl phydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the subject or animal as is known in the art.

The unit dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable salt thereof, in asuitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at, inone embodiment, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (including butnot limited to 10-1000 mg or 100-500 mg) or multiple dosages of thecompound. The lyophilized powder can be stored under appropriateconditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg oflyophilized powder, is added per mL of sterile water or other suitablecarrier. The precise amount depends upon the selected compound. Suchamount can be empirically determined.

Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsion or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable salts thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will have diameters of less than50 microns or less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono, di andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. An exemplary weight of a rectalsuppository is about 2 to 3 grams.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

Sustained Release Compositions

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108,5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830,6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981,6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634,each of which is incorporated herein by reference. Such dosage forms canbe used to provide slow or controlled-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients provided herein.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. In one embodiment, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. In certain embodiments,advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased subject compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used(see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989). In another embodiment, polymeric materials can be used. In yetanother embodiment, a controlled release system can be placed inproximity of the therapeutic target, i.e., thus requiring only afraction of the systemic dose (see, e.g., Goodson, Medical Applicationsof Controlled Release, vol. 2, pp. 115-138 (1984).

In some embodiments, a controlled release device is introduced into asubject in proximity of the site of inappropriate immune activation or atumor. Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990). The active ingredient can bedispersed in a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the needs of thesubject.

Targeted Formulations

The compounds provided herein, or pharmaceutically acceptable saltsthereof, may also be formulated to be targeted to a particular tissue,receptor, or other area of the body of the subject to be treated,including liposome-, resealed erythrocyte-, and antibody-based deliverysystems. Many such targeting methods are well known to those of skill inthe art. All such targeting methods are contemplated herein for use inthe instant compositions. For non-limiting examples of targetingmethods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359,6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082,6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252,5,840,674, 5,759,542 and 5,709,874.

In one embodiment, the antibody-based delivery system is anantibody-drug conjugate (“ADC”), e.g., as described in Hamilton G S,Biologicals, 2015 September, 43(5):318-32; Kim E G and Kim K M, Biomol.Ther. (Seoul), 2015 Nov. 23(6):493-509; and Peters C and Brown S,Biosci. Rep., 2015 Jun. 12, 35(4) pii: e00225, each of which isincorporated herein by reference.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. For example, liposomeformulations may be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) may be formedby drying down egg phosphatidyl choline and brain phosphatidyl serine(7:3 molar ratio) on the inside of a flask. A solution of a compoundprovided herein in phosphate buffered saline lacking divalent cations(PBS) is added and the flask shaken until the lipid film is dispersed.The resulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

Articles of Manufacture

The compounds or pharmaceutically acceptable salts can be packaged asarticles of manufacture containing packaging material, a compound orpharmaceutically acceptable salt thereof provided herein, which is usedfor treatment, prevention or amelioration of one or more symptoms orprogression of a disease or disorder disclosed herein, and a label thatindicates that the compound or pharmaceutically acceptable salt thereofis used for treatment, prevention or amelioration of one or moresymptoms or progression of a disease or disorder disclosed herein.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, pens,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment. A wide array offormulations of the compounds and compositions provided herein arecontemplated.

In certain embodiments, provided herein also are kits which, when usedby the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a subject. In certainembodiments, the kit provided herein includes a container and a dosageform of a compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

6.7. Dosing

The compounds and pharmaceutical compositions provided herein may bedosed in certain therapeutically or prohylactically effective amounts,certain time intervals, certain dosage forms, and certain dosageadministration methods as described below.

In certain embodiments, a therapeutically or prophylactically effectiveamount of the compound is from about 0.005 to about 1,000 mg per day,from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mgper day, from about 0.01 to about 100 mg per day, from about 0.1 toabout 100 mg per day, from about 0.5 to about 100 mg per day, from about1 to about 100 mg per day, from about 0.01 to about 50 mg per day, fromabout 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day,from about 1 to about 50 mg per day, from about 0.02 to about 25 mg perday, from about 0.05 to about 10 mg per day, from about 0.05 to about 5mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 toabout 5 mg per day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is about 0.1, about 0.2, about 0.5, about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 15, about 20, about 25, about 30, about 40, about 45, about 50,about 60, about 70, about 80, about 90, about 100, or about 150 mg perday.

In one embodiment, the recommended daily dose range of the compoundprovided herein, or a derivative thereof, for the conditions describedherein lie within the range of from about 0.5 mg to about 50 mg per day,in one embodiment given as a single once-a-day dose, or in divided dosesthroughout a day. In some embodiments, the dosage ranges from about 1 mgto about 50 mg per day. In other embodiments, the dosage ranges fromabout 0.5 to about 5 mg per day. Specific doses per day include 0.1,0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

In a specific embodiment, the recommended starting dosage may be 0.5, 1,2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, therecommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. Thedose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In aspecific embodiment, the compound can be administered in an amount ofabout 25 mg/day. In a particular embodiment, the compound can beadministered in an amount of about 10 mg/day. In a particularembodiment, the compound can be administered in an amount of about 5mg/day. In a particular embodiment, the compound can be administered inan amount of about 4 mg/day. In a particular embodiment, the compoundcan be administered in an amount of about 3 mg/day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is from about 0.001 to about 100 mg/kg/day, from about0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, fromabout 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day,0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, fromabout 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day,from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 toabout 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.

The administered dose can also be expressed in units other thanmg/kg/day. For example, doses for parenteral administration can beexpressed as mg/m²/day. One of ordinary skill in the art would readilyknow how to convert doses from mg/kg/day to mg/m²/day to given eitherthe height or weight of a subject or both (see,www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1mg/kg/day for a 65 kg human is approximately equal to 38 mg/m²/day.

In certain embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 0.001 to about 500 μM, about 0.002 to about200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, fromabout 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 toabout 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20μM, or from about 1 to about 20 μM.

In other embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 5 to about 100 nM, about 5 to about 50 nM,about 10 to about 100 nM, about 10 to about 50 nM or from about 50 toabout 100 nM.

As used herein, the term “plasma concentration at steady state” is theconcentration reached after a period of administration of a compoundprovided herein, or a derivative thereof. Once steady state is reached,there are minor peaks and troughs on the time dependent curve of theplasma concentration of the compound.

In certain embodiments, the amount of the compound administered issufficient to provide a maximum plasma concentration (peakconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM,from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, fromabout 0.5 to about 20 μM, or from about 1 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide a minimum plasma concentration (troughconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM,from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, fromabout 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide an area under the curve (AUC) of the compound,ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 toabout 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, orfrom about 5,000 to about 10,000 ng*hr/mL.

The methods provided herein encompass treating a patient regardless ofsubject's age, although some diseases or disorders are more common incertain age groups.

Depending on the disease to be treated and the subject's condition, thecompound provided herein, or a derivative thereof, may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,CIV, intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration. The compoundprovided herein, or a derivative thereof, may be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants and vehicles, appropriate for each routeof administration.

In one embodiment, the compound provided herein, or a derivativethereof, is administered orally. In another embodiment, the compoundprovided herein, or a derivative thereof, is administered parenterally.In yet another embodiment, the compound provided herein, or a derivativethereof, is administered intravenously.

The compound provided herein, or a derivative thereof, can be deliveredas a single dose such as, e.g., a single bolus injection, or oraltablets or pills; or over time, such as, e.g., continuous infusion overtime or divided bolus doses over time. The compound can be administeredrepeatedly if necessary, for example, until the subject experiencesstable disease or regression, or until the subject experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205 216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or MRI scan and other commonly accepted evaluation modalities.

The compound provided herein, or a derivative thereof, can beadministered once daily (QD), or divided into multiple daily doses suchas twice daily (BID), three times daily (TID), and four times daily(QID). In addition, the administration can be continuous (i.e., dailyfor consecutive days or every day), intermittent, e.g., in cycles (i.e.,including days, weeks, or months of rest without drug). As used herein,the term “daily” is intended to mean that a therapeutic compound, suchas the compound provided herein, or a derivative thereof, isadministered once or more than once each day, for example, for a periodof time. The term “continuous” is intended to mean that a therapeuticcompound, such as the compound provided herein or a derivative thereof,is administered daily for an uninterrupted period of at least 10 days to52 weeks. The term “intermittent” or “intermittently” as used herein isintended to mean stopping and starting at either regular or irregularintervals. For example, intermittent administration of the compoundprovided herein or a derivative thereof is administration for one to sixdays per week, administration in cycles (e.g., daily administration fortwo to eight consecutive weeks, then a rest period with noadministration for up to one week), or administration on alternate days.The term “cycling” as used herein is intended to mean that a therapeuticcompound, such as the compound provided herein or a derivative thereof,is administered daily or continuously but with a rest period. In somesuch embodiments, administration is once a day for two to six days, thena rest period with no administration for five to seven days.

In some embodiments, the frequency of administration is in the range ofabout a daily dose to about a monthly dose. In certain embodiments,administration is once a day, twice a day, three times a day, four timesa day, once every other day, twice a week, once every week, once everytwo weeks, once every three weeks, or once every four weeks. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once a day. In another embodiment, the compound providedherein, or a derivative thereof, is administered twice a day. In yetanother embodiment, the compound provided herein, or a derivativethereof, is administered three times a day. In still another embodiment,the compound provided herein, or a derivative thereof, is administeredfour times a day.

In certain embodiments, the compound provided herein, or a derivativethereof, is administered once per day from one day to six months, fromone week to three months, from one week to four weeks, from one week tothree weeks, or from one week to two weeks. In certain embodiments, thecompound provided herein, or a derivative thereof, is administered onceper day for one week, two weeks, three weeks, or four weeks. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once per day for 4 days. In one embodiment, the compoundprovided herein, or a derivative thereof, is administered once per dayfor 5 days. In one embodiment, the compound provided herein, or aderivative thereof, is administered once per day for 6 days. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once per day for one week. In another embodiment, thecompound provided herein, or a derivative thereof, is administered onceper day for two weeks. In yet another embodiment, the compound providedherein, or a derivative thereof, is administered once per day for threeweeks. In still another embodiment, the compound provided herein, or aderivative thereof, is administered once per day for four weeks.

Combination Therapy With A Second Active Agent

The compound provided herein, or a derivative thereof, can also becombined or used in combination with other therapeutic agents useful inthe treatment and/or prevention of cancers, inflammatory diseases,rasopathies, or fibrotic disease.

In one embodiment, provided herein is a method of treating, preventing,or managing cancers, inflammatory diseases, rasopathies, and fibroticdisease, comprising administering to a subject a compound providedherein, or a derivative thereof; in combination with one or more secondactive agents.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein, a compound provided herein, e.g., the compound providedherein, or a derivative thereof) can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of asecond therapy (e.g., a prophylactic or therapeutic agent) to thesubject. Triple therapy is also contemplated herein.

Administration of the compound provided herein, or a derivative thereofand one or more second active agents to a subject can occursimultaneously or sequentially by the same or different routes ofadministration. The suitability of a particular route of administrationemployed for a particular active agent will depend on the active agentitself (e.g., whether it can be administered orally without decomposingprior to entering the blood stream) and the disease or disorder beingtreated.

The route of administration of the compound provided herein, or aderivative thereof, is independent of the route of administration of asecond therapy. In one embodiment, the compound provided herein, or aderivative thereof, is administered orally. In another embodiment, thecompound provided herein, or a derivative thereof, is administeredintravenously. Thus, in accordance with these embodiments, the compoundprovided herein, or a derivative thereof, is administered orally orintravenously, and the second therapy can be administered orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form. In one embodiment, the compound provided herein, or aderivative thereof, and a second therapy are administered by the samemode of administration, orally or by IV. In another embodiment, thecompound provided herein, or a derivative thereof, is administered byone mode of administration, e.g., by IV, whereas the second agent isadministered by another mode of administration, e.g., orally.

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount of the compound provided herein, or a derivative thereof, andany optional additional active agents concurrently administered to thesubject.

One or more second active ingredients or agents can be used togetherwith the compound provided herein, or a derivative thereof, in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies, particularly, therapeutic antibodies to cancerantigens. Typical large molecule active agents are biological molecules,such as naturally occurring or synthetic or recombinant proteins.

In one embodiment, the compound provided herein, or a derivativethereof, can be administered in an amount ranging from about 0.1 toabout 150 mg, from about 1 to about 25 mg, or from about 2 to about 10mg orally and daily alone, or in combination with a second active agent,prior to, during, or after the use of conventional therapy.

7. EXAMPLES

The following examples are offered to illustrate but not to limit thedisclosure.

Example 1 Computational Procedure for Modeling

The protein structures used in this work were obtained from the RCSB PDB(www.rcsb.org).

These structures were prepared for modeling using a suite of structurepreparation tools available in the Molecular Operating Environmentsoftware (MOE). MOE is a state of the art molecular modeling packagelicensed by Chemical Computing Group (Molecular Operating Environment(MOE), 2016.08; Chemical Computing Group Inc., 1010 Sherbrooke St. West,Suite #910, Montreal, QC, Canada, H3A 2R7, 2016). It is used extensivelyin the pharmaceutical industry to carry out a wide range ofcomputer-aided drug design activities. Specifically, each structure wasexamined for missing atoms and chain breaks. Where possible these werecorrected by modeling in incomplete residues or capping. The ligand wasalso evaluated to ensure the correct structure and bond orders. Alltitratable residues and the ligand were subjected to Protonate3D(Labute, P.; Protonate3D: Assignment of Ionization States and HydrogenCoordinates to Macromolecular Structures; Proteins 75 (2008) 187-205) todetermine the most probably protonation states at pH 7. Finally, theenvironment around the ligand was subjected to restrained optimizationto remove bad intermolecular contacts and reduce the strain energy forthe ligand.

Compounds of interest were modeled in the appropriate binding site usinga variety of methods all available in MOE. In many cases the ligands hadto be docked into the site. Docking is an automated approach to examineall of the possible ways a ligand might fit into a protein binding siteof interest and score the possibilities. These scored structures wereused to suggest the best overall protein-ligand complex structure.Docked structures can be evaluated further using other energetic orstructural evaluations. In many cases, we also computed the location andcontributions of water molecules to binding. This analysis based on3D-RISM calculations (Luchko, T., Gurasov, S., Roe, D. R., Simmerling,C., Case, D. A., Tuszynski, J., Kovalenko, A.; Three-DimensionalMolecular Theory of Solvation Coupled with Molecular Dynamics in Amber;J. Chem. Theory Comput. 6 (2010) 607-624) can be very helpful forunderstanding water mediated interactions, and new potential bindingsites in the protein that might be exploited with appropriatesubstitution of the putative ligand.

The ability to build computational models before undertaking theirsynthesis is a powerful tool for improving the speed and success of drugdiscovery (Merz, Kenneth M.; Ringe, Dagmar; Reynolds, Charles H.,Editors, Drug design: ligand and structure based approaches, CambridgeUniversity Press, 2010).

The docking models displayed in the figures include residues with anyatom in close proximity to within a 2.5 angstrom distance from any atomin the ligand. In addition, residues within approximately 2.5 angstromsfrom the ligand with specific interactions (i.e., a hydrogen bond) areincluded, and highlighted in the 2D interaction maps.

FIG. 1 displays GDP bound to the GTP binding site of KRas as determinedby the crystal structure of GDP with KRas, PDB code: 4epr. The KRasresidues within 2.5 angstroms of the ligand or approximately 2.5angstroms from the ligand with specific interactions are Gly13, Gly15,Lys16, Ser17, Ala18, Val29, Asp30, Asn116, Asp119, Leu120, Ser145,Ala146 and Lys147.

FIG. 2 depicts a compound disclosed herein binding to the guanosinebinding region of the GTP binding site of KRas as determined throughmolecular modeling of a compound disclosed herein with KRas crystalstructure PDB code: 4epr. The KRas residues within 2.5 angstroms of theligand or approximately 2.5 angstroms from the ligand with specificinteractions are Ala18, Asp30, Pro34, Lys117, Asp119, Leu120, Ala146 andLys147.

FIG. 3 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of KRas as determined through molecular modelingof a compound disclosed herein with KRas crystal structure PDB code:4epr. The KRas residues within 2.5 angstroms of the ligand orapproximately 2.5 angstroms from the ligand with specific interactionsare Asp12, Gly13, Ala18, Pro34, Asp119, Leu120, Lys147 and Mg202.

FIG. 4 depicts a compound disclosed herein binding to the guanosinebinding site of the alternative Tyr32 conformation in the GTP bindingsite of KRas as determined through molecular modeling of a compounddisclosed herein with KRas crystal structure PDB code: 3gft. The KRasresidues within 2.5 angstroms or approximately 2.5 angstroms from theligand with specific interactions of the ligand are Gly15, Ser17, Ala18,Phe28, Asp30, Tyr32, Asp119, Ala146 and Lys147.

FIG. 5 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation “Tyr conformation” in the GTPbinding site of KRAS as determined through molecular modeling of acompound disclosed herein with KRas crystal structure PDB code: 3gft.The KRas residues within 2.5 angstroms or approximately 2.5 angstromsfrom the ligand with specific interactions of the ligand are Gly13,Gly15, Ser17, Ala18, Tyr32, Asp33, Lys117, Lys147 and Mg202.

FIG. 6 depicts a compound disclosed herein binding to the guanosinebinding site of the GTP binding site of KRas as determined throughmolecular modeling of a compound disclosed herein with KRas crystalstructure PDB code: 4epr. The KRas residues within 2.5 angstroms orapproximately 2.5 angstroms from the ligand with specific interactionsof the ligand are Gly15, Phe28, Asn116, Asp119, Leu120, and Lys147.

FIG. 7 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of KRas as determined through molecular modelingof a compound disclosed herein with KRAS crystal structure PDB code:4epr. The KRas residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areAsp12, Gly13, Ala18, Pro34 and Mg202.

FIG. 8 depicts a compound disclosed herein binding to the guanosinebinding site of the alternative Tyr32 conformation in the GTP bindingsite of KRas as determined through molecular modeling of a compounddisclosed herein with KRas crystal structure PDB code: 3gft. The KRasresidues within 2.5 angstroms or approximately 2.5 angstroms from theligand with specific interactions of the ligand are Gly15, Tyr32,Lys117, Asp119, Ala146 and Lys147.

FIG. 9 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft. The KRas residues within 2.5angstroms or approximately 2.5 angstroms from the ligand with specificinteractions of the ligand are Gly13, Gly15, Ser17, Ala18, Asp30, Tyr32,Asp33 and Mg 202.

FIG. 10 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft. The KRas residues within 2.5angstroms or approximately 2.5 angstroms from the ligand with specificinteractions of the ligand are Ala11, Gly12, Lys16, Ser17, Tyr32, Thr35,Lys36, Lys117, Asp119 and Mg 202.

FIG. 11 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft. The KRas residues within 2.5angstroms or approximately 2.5 angstroms from the ligand with specificinteractions of the ligand are Gly12, Val14, Gly15, Lys16, Ser17, Phe28,Val29, Glu31, Thr35, Gly60, Lys117, Leu120 and Mg 202.

FIG. 12 depicts a compound disclosed herein binding to the metal regionof the alternative Tyr32 conformation in the GTP binding site of KRas asdetermined through molecular modeling of a compound disclosed hereinwith KRas crystal structure PDB code: 3gft. The KRas residues within 2.5angstroms or approximately 2.5 angstroms from the ligand with specificinteractions of the ligand are Ala11, Gly12, Gly15, Ser17, Ala18, Val29,Tyr32, Asp33, Thr35 and Mg 202.

FIG. 13 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rac-1 as determined through molecularmodeling of a compound disclosed herein with Rac-1 crystal structure PDBcode: 2p21. The Rac-1 residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areAla13, Gly15, Lys16, Thr17, Cys18, Lys116, Asp118, Leu 119 and Mg 202.

FIG. 14 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rac-1 as determined through molecularmodeling of a compound disclosed herein with Rac-1 crystal structure PDBcode: 2p21. The Rac-1 residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areGly12, Ala13, Thr17, Ile33, Pro34, Val36, Ala59 and Mg 202.

FIG. 15 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rac-1 as determined through molecularmodeling of a compound disclosed herein with Rac-1 crystal structure PDBcode: 2p21. The Rac-1 residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areAla13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Thr115, Cys157,Ala159 and Mg 202.

FIG. 16 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rho-A as determined through molecularmodeling of a compound disclosed herein with Rho-A crystal structure PDBcode: 5hpy. The Rho-A residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areCys16, Gly17, Lys18, Thr19, Phe30, Pro31, Val35, Lys118, Asp120 and Mg202.

FIG. 17 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rho-A as determined through molecularmodeling of a compound disclosed herein with Rho-A crystal structure PDBcode: 5hpy. The Rho-A residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areGly14, Ala15, Lys18, Thr19, Cys20, Pro31, Glu32, Tyr34, Val35, Pro36,Thr37 and Mg 202.

FIG. 18 depicts a compound disclosed herein binding to the metal regionof the GTP binding site of Rho-A as determined through molecularmodeling of a compound disclosed herein with Rho-A crystal structure PDBcode: 5hpy. The Rho-A residues within 2.5 angstroms or approximately 2.5angstroms from the ligand with specific interactions of the ligand areGly17, Thr19, Phe30, Tyr34, Pro36, Thr37, Asp59, Lys118, Lys162 and Mg202.

Example 2 Protocol for MAPK Cell-Based Phosphorylation Assay

Cell lines: Tumor-derived pancreatic cancer cell lines PANC-1 werepurchased from ATCC and were maintained according to ATCCrecommendation.

Method: Cells were plated at 7500 cells/well density in 96-wells plate,starved over night, and the small molecules to be tested were added tothe cells in the final concentration of 30 μM with 0.3% DMSO for 6 hoursincubation at 37° C. For IC₅₀ value determination, serial dilutions ofcompounds were added to cells under the same conditions. Next, cellswere stimulated with 1.5 ng/ml EGF for 15 min. followed by cell fixationwith 4% Formaldehyde in PBS at RT for 20 min. Phosphorylation level ofMAPK was determined by Cell-direct ELISA.

Cell-direct ELISA: For each well, cells were permeabilized withPBS-Triton 0.1%, quenched with H₂O₂ 0.6% in PBS-Triton 0.1%, and probedwith anti-phospho-MAPK antibodies (R&D Systems) followed byHRP-conjugated secondary antibody (Jackson Immunoresearch, West Grove,Pa.). Next, a solution 50 μM of the fluorescent substrate AmpliFlu Red(Sigma) was added and incubated at RT for 20 min. At the end of theincubation time, fluorescence was measured at 595 nm on a microplatereader (AF2200; Eppendorf, Inc., Hamburg, Germany).

Table 4 shows inhibition data for selected compounds tested in thecellular assay described above.

TABLE 4 % Inhibition of MAPK phosphorylation at 30 μM in the PANC-1pancreatic cancer cell line, and select IC₅₀ data IC₅₀ Compound PANC-1(μM)

B

A

C

A

C

A

A

A

A

B

A

A

A

A

A

B

A

B

A

A

A

C

B

A

A

C

A

A

A

A

A

A

B

A

A

A

B

A

A

B

A

A

B

A

B

B

D

A

D F

D G

B

A

A

B

A

D

A

A

B

A

A

B

A

D

A

A

B

A

B

A

A

A

D G

A

A

A

D G

B

A

A

B

A

D H

D H

A

A

A

A

D G

A F

A

D G

C

A

D

A

A

B

B

D G

A

A

A

B

B

B

B

A

A

D

C

A

A

A

A

A

D

B

B

A

A

A

C E

B

A

A

D E

A

B

A

A

B E

A

C E

A

A

A E

B E

A

A

A

D G

A

B

A

A

A

A

A

A

A

C E

A

B

B

B

A

A

A

B

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

B

B

B

B

C

A

B

D

A

A

B

A

A

B

A

A

A*

A*

A*

A*

B*

D* G

D* G

A* E

D* H

B*

A*

A*

A*

B*

A*

B*

B*

A*

B*

C*

A*

A*

D* G

A*

A*

D* G

A*

D* H

B*

D* H

C*

C*

A*

D*

D*

D*

D*

A*

C*

B*

A*

A*

B*

A*

B*

A*

A*

B*

D*

B*

A*

B*

D*

D*

A*

A*

D*

A*

B*

A*

B*

B*

A*

A*

B*

D*

A*

A*

D*

D*

D*

D*

C*

C*

C*

B*

0*

0*

0*

0*

0*

0*

0*

0*

A*

A*

B*

B*

B*

C*

D*

A*

B*

C*

0*

0*

C*

D*

0*

0*

0*

A*

A*

B*

B*

0*

A*

C*

0*

A*

D*

0*

0*

A*

0*

B*

0*

0*

0*

A*

0*

0*

0*

0*

0*

A*

A*

0*

0*

A*

D*

A*

A*

A*

B*

A*

0*

B*

A*

B*

A*

D*

D*

D*

A*

D*

D*

0*

D*

A*

D*

D*

D*

B*

A*

D*

D*

0*

D*

C*

B*

D*

C*

C*

D*

C*

C*

0*

C*

0*

C*

B*

C*

B*

A*

B*

B*

A*

B*

A*

A*

A*

A*

A*

B*

B*

B*

B*

C*

D*

B*

0*

B*

B*

B*

0*

0*

C* *= tested at 10 μM. A = 1-25% inhibition, B = 25-50% inhibition, C =51-75% inhibition, D = 76-100% inhibition. E = >30 μM IC₅₀, F = 11-30 μMIC₅₀, G = 2-10 μM IC₅₀, H = <2 μM IC₅₀.

Example 3 Protocol for Cell Proliferation Assay

Cell lines: Tumor-derived pancreatic cancer cell lines MIA-PACA2 werepurchased from ATCC and grown in complete DMEM-High Glucose mediumsupplemented with penicillin (100 U/mL), streptomycin (100 μg/mL), and10% heat-inactivated FBS at 37° C. in a humidified incubator with 5%CO₂.

Method: Cells are plated at 1000 cells/well density in 96-wells plate,starved ON, and the next day tested small molecules are added to thecells in the final concentration of 30 μM with 0.3% DMSO 3 hours priorto 10% FBS addition. After serum addition cells are incubated for 6 daysat 37° C. in a humidified incubator with 5% CO₂. For IC₅₀ valuedetermination, serial dilutions of compounds were added to cells underthe same conditions.

Assay: At the end of the incubation period, cell cultures are testedusing the CellTiter 96® AQueous One Solution Cell Proliferation Assaykit (Promega Corporation, Madison, Wis.) according to the manufacturerspecifications. Briefly, assay is performed by adding 20 μl of theCellTiter 96 Aqueous One Solution Reagent directly to culture wells,followed by for 1-4 hours incubation at 37° C. in a humidified incubatorwith 5% CO₂. At the end of incubation time, absorbance at 492 nm isrecorded with the 96-well plate reader Eppendorf AF2200, and degree ofsmall molecule-dependent proliferation inhibition is calculated from rawdata assuming No Serum cells value as 100%.

Alternate Assay Conditions

Cell lines: Tumor-derived pancreatic cancer cell lines MIA-PACA2 werepurchased from ATCC and grown in complete DMEM-High Glucose mediumsupplemented with penicillin (100 U/mL), streptomycin (100 μg/mL), and10% heat-inactivated FBS at 37° C. in a humidified incubator with 5%CO₂.

Method: Cells are plated at 4000 cells/well density in 96-wells plate.The next day tested small molecules are added to the cells in the finalconcentration of 10 μM in the presence of 0.3% DMSO and 10% FBS. Aftersmall molecules addition, cells are incubated for 4 days at 37° C. in ahumidified incubator with 5% CO₂. For IC₅₀ value determination, serialdilutions of compounds were added to cells under the same conditions.

Assay: At the end of the incubation period, cell cultures are fixed witha 50-50 mixture (v/v) acetone—methanol for 10 minutes at −20° C.,followed by rehydration in PBS for 10 minutes at room temperature. Afterrehydration, cells are stained with DAPI (1 μg/ml) in PBS for 10 minutesat room temperature, followed by 3 washes with PBS. After staining, DAPIfluorescence is recorded (358 nm excitation/461 nm emission) with the96-well plate reader Molecular Devices Spectramax M3; degree of smallmole-cule-dependent proliferation inhibition is calculated from raw dataassuming No Serum cells value as 100%.

Table 5 shows inhibition data for selected compounds tested in thecellular assay conditions described above.

TABLE 5 % Inhibition of cell proliferation at 30 μM or 10 μM inMIA-PACA2 pancreatic cancer cell lines, with select IC₅₀ valuesMIA-PACA2 (alternate IC₅₀ Compound MIA-PACA2 conditions) (nM)

D

B

A

D

A

C

A

B

C

C

D

D

D

D

D

C

D

C

B

B

D

D

A

B

C

D

A

C

B

B

A

C

A

D

D

D

C

C

D

A

D

D

D

D

C

C

B

D

D

C

D

D

B

C

D

A

D

B

B

D

D

D

C

C

B

B

C

A

D

A

D

D

B

B

D

D

D

D

C

A

D

C

D

C

A

D

D

B

A

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

C

D

D

A E

D

D

C

A

D

D

D

D

D

D

D

D

A

D

D

D E

D

B

D

D

D

D

D

D

D

A

D

D

D

D

D

D

D

D

D

C

D

B

D

A

D

C

C

D

A

D

C

A

D

D

D

D

D

D

A

D

A

A

B

D

D

D

A

A

B

A

A

D F

D

D

D

D

A

A

D G

D

D

D

A

C

B

A

B

D

D

B

D G

D G

B

D

A

D

B

C

D G

D

D

D

A

C

D F

D

D

D

D

D

D

D

D

D

D

D E

A

D

C

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

A

A

D G

D G

D

D

D

D

D G

D

C

D

C

D

D

B

D

D

D

D

D

B

C

D

D

D F

D

D

A

D

D

D

D

D

D

D

D

D

B

D

D

A

D

D

D

D

D

C

D

D

C

D

D

D

D

D

D

D

D

D

D

D

D

D

D

C

D

D

D

C

D

D

D

A

D

D

D

A

C

B

D

A

D

D

D

D

D

D

D

D

D

D

D G

D D* H

D G

D G

D G

C

D

B

C

A

D

D

C

A

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D D* G

D

D

D

D D* F

D

D

D

D

D

D

D

D

D

D

D

D

C

D

B

D

A

D

D D* E

D

A

B

D

D

D

D

D

D

A

D

D

D

D

D

D

D

D

D

C

D

D

D*

A*

D*

D*

D*

D*

0*

D*

D*

D*

D*

D*

D*

D*

B*

B*

D*

D*

D*

A*

C*

D*

D*

0*

0*

D*

B*

C*

B*

D*

0*

0*

D*

0*

D*

D*

D*

D*

D*

D*

A*

D*

D* F

D*

B*

D*

D*

D*

C*

0*

A*

C*

A*

A*

B*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

D*

A*

D* E

D*

D*

D*

D* F

D* F

D*

D*

C*

D* F

D*

D* F

D*

D*

D* E

D* F

D*

D* E

D* F

D*

D*

D* G

C*

D* F

D*

D*

B*

D* F

D*

D* G

D*

D* G

D* E

D* G

D*

B*

D* G

D* G

D*

D*

D*

D* E

D*

D*

D*

D*

D* G

D*

D*

D*

D*

D*

D*

D*

D*

D*

D* F * = tested at 10 μM Note: IC₅₀ values were determined via the sameassay as was used for the % inhibition determination for each compoundreported. A = 1-25% inhibition, B = 25-50% inhibition, C = 51-75%inhibition, D = 76-100% inhibition. E = >1000 nM IC₅₀, F = 501-1000 nMIC₅₀, G = 100-500 nM IC₅₀, H = <100 nM IC₅₀.

Example 4 Protocol for Mouse TNF Alpha and IL6 Quantification Assay

Cell lines: Abelson murine leukemia virus transformed macrophage cellline RAW 264.7 was purchased from ATCC and grown in complete DMEM-HighGlucose medium supplemented with penicillin (100 U/mL), streptomycin(100 μg/mL), and 10% heat-inactivated FBS at 37° C. in a humidifiedincubator with 5% CO₂.

Method: Cells were plated at 40000 cells/well density in a 96-wellsplate. After a 3-hour incubation, macrophages were starved with DMEMplus 0.5% FBS o/n. The next day the small molecules to be tested wereadded to the cells in the final concentration of 30 μM (with 0.3% DMSO)3 hours prior to LPS stimulation (100 ng/ml). After LPS stimulationcells were incubated at 37° C. for 16 h. At the end of the incubationperiod, culture media were collected and production of LPS-induced TNFαand IL6 cytokine was measured using ELISA detection kits.

Sandwich ELISA: The ELISA Immunoassays Quantikine Mouse TNF-alpha(catalog number MTA00B) and IL6 (catalog number M6000B) were purchasedfrom R&D Systems Inc., Minneapolis, Minn. These 4.5 hours solid phaseELISAs were used to measure mouse TNFα or IL6 levels in macrophagesculture supernatants. Assays were executed according to the manufacturerspecifications.

Table 6 shows inhibition data for selected compounds tested in thecellular assay described above.

TABLE 6 IL-6 and TNFα % Inhibition at 30 μM in RAW 264.7 murine leukemiavirus transformed macrophage cell lines Compound IL-6 TNF-α

B A

0 A

0 A

0 A

A B

A 0

B A

0 A

B A

A A

A A

0 A

B A

B 0

A 0

B A

C 0

A 0

A 0

C A

0 A

A 0

C A

0 A

A 0

0 A

0 A

A 0

A A

A 0

B A

B A

A 0

A 0

0 A

A 0

A 0

A A

B A

A 0

A 0

0 A

A 0

A 0

0 A

A A

A 0

A 0

B A

A A

A 0

A 0

A A

A 0

A A

0 A

A A

B 0

A 0

0 A

B A

B A

A A

B A

A A

0 A

A 0

B A

A 0

C 0

C A

B A

0 A

0 A

B 0

B 0

A 0

B A

B A

B A

0 A

A 0

0 A

A 0

D 0

C 0

C 0

B A

0 A

C A

C A

B A

A A

A A

B A

B B

A 0

D C

B A

0 A

0 A

0 A

A 0

C D

A A

D D

A A

A A

B B

0 A

0 A

0 A

0 A

A 0

D D

D D

B 0

B A

B A

A A

A A

B 0

B A

B A

A 0

A 0

A 0

0 A

C 0

B B

D D

0 A

C A

0 A

A A

0 A

A C

C 0

B 0

A A

B 0

B B

A B

0 A

A 0

B A

D A

C A

D B

A 0

D A

D B

D A

D A

C 0

D A

A A

B 0

B 0

0 A

D B

B 0

A A

D A

A A

A A

0 A

0 A

0 A

A 0

0 A

A 0

A 0

A A

A A

D D

B 0

D A

D A

C A

A 0

A B

D C

A 0

D A

C 0

A 0

C 0

B 0

C 0

B 0

C 0

B A

A 0

B 0

D C

D D

D D

A 0

B 0

A A

C 0

A A

D D

C A

A 0

A A

D D

D D

A 0

D D

D D

B B

A A

D C

C B

D B

D C

D D

A A

A A

A A

B A

B A

B B

D C

D B

A 0

B 0

B A

A A

B A

A A

D B

C B

A A

D D

B B

A A

A A

A A

A A

B 0

C A

B A

B A

C A

D B

B 0

A 0

A 0

A 0

A 0

D A

D 0

B 0

C 0

B 0

B A

D 0

D 0

D B

D 0

C 0

A A

D A

C 0

D C

D A

D A

D 0

B 0

D A

C 0

D A

D A

D D

D A

A 0

A 0

A A

A 0

B 0

A A

A A

C 0

C A

0 A

B 0

B 0

C 0

C 0

A 0

A 0

B 0

D C

D A

C A

A A

B A

B A

C A

0 A

D A

A A

C A

C 0

D A

D B

B 0

A A

B A

D C

D C

D C

D D

0 A

C C

A A

B B

A A

B 0

C 0

A 0

D 0

B 0

D C

D B

D A

D B

D 0

D A

C 0

D B

D 0

D C

C 0

D C

D B

D B

D D

D B

D D

D B

D C

D 0

D D

D D

D D

B 0

D D

C A

B 0

D A

D D

D B

C 0

A 0

B 0

B 0

A 0

A 0

C 0

D D

B 0

A 0

B B

D C

D C

A 0

D C

C 0

D D

A A

D C

D A

B 0

C 0

D A

A 0

D A

C 0

D A

A A

0 0

B A

D A

D C

D D

A 0

0 A

D D

B A

A A

D A

C 0

A 0

D A

D D

C 0

B 0

B 0

D C

D B

B 0

D C

B 0

B A

A 0

B 0

D A

0 0

C B

D D

B 0

A 0

D B

C C

A 0

A A

A A

D A

A 0

0 A

B 0

0 A

A A

D A

C A

A B

0 A

0 A

C A

C A

0 0

A B

0 B

C B

A B

A 0

D C

C A

D D

0 B

A A

0 0

0 0

0 0

C 0

0 0

A 0

A 0

A 0

0 0

A A

A 0

0 A

A A

B 0

A B

A A

C A

0 A

B A

B A

0 A

A A

0 A

D D

A A

B A

B 0

D D

D D

A B

D D

D C

D D

D D

D D

C A

C B

C A

A A

D C

D D

A B

A B

D D

C A

A 0

D C

D D

B B

B B

B B

D B

D C

C A

D C

D C

0 0

A A

A A

B A

D C

0 0

D B

0 0

B 0

A B

A 0

C 0

A 0

D D

D D

D C

C A

C A

C 0

B 0

A 0

0 0

C 0

D D 0 = 0% inhibition, A = 1-25% inhibition, B = 26-50% inhibition, C =51-75% inhibition, D = 76-100% inhibition.

Example 5 Ras GTP Binding Domain Inhibition Assay

The following method was developed as specific assay for KRas G12Dmutant protein.

Buffer-I:

-   -   50 mM Tris, pH 7.5    -   150 mM NaCl (optional)    -   1 mM MgCl₂    -   1 mM DTT.

KRas G12D mutant protein was expressed as a His-tagged protein. PurifiedHis-KRas G12D protein was diluted in buffer-I to a final concentrationof 3-10 μg/ml.

200 μl of the diluted His-KRas G12D protein was added to a nickel coated96 well plate and incubated overnight at 4° C.

The next day, wells were washed 3× in 200 μl of Buffer-I.

Then 200 μl of Buffer-I were added to each well in the presence of 1%DMSO.

Tested compounds were added to the protein-coated wells at aconcentration of 20 μM, and incubated for 3 hours at room temperature.While performing IC₅₀ measurements a serial dilution of all testedconcentrations was prepared.

Then 22 μl of Cy3-GTP or Cy5-GTP was added to each well. The labeled GTPwas incubated for 45 min. at room temperature.

Following GTP incubation, wells were washed 3× in Buffer-I, and 200 μlof Buffer-I were added to each well.

Following washes, the amount of bound labeled-GTP was measured with anEppendorf AF2200 plate reader.

By substituting KRas G12D mutant protein with KRas G12C mutant, KRaswild type, KRas Q61H mutant, KRas G12D/Q61H double mutant or KRasG12C/Q61H double mutant under the assay conditions described above, KRasG12C mutant KRas wild type, KRas Q61H mutant, KRas G12D/Q61H doublemutant and KRas G12C/Q61H double mutant inhibition, respectively, wereeach determined.

Table 7 shows inhibition data for selected compounds tested in thescreening assay described above.

TABLE 7 % Inhibition at 20 μM of K-Ras mutant and wild-type protein KRasKRas KRas KRas KRas KRas wild G12D G12C KRas G12D G12D G12C type, Q61HQ61H Q61H Q61H % % % % % % IC₅₀ Structure Inh. Inh. Inh. Inh. Inh. Inh.(μM)

C

C

C

C

C

C

C

C

C

C

C

C

C

C

D C C D

C

C

C

C

B B B C

C

C H

D B C D

C

D

B

B

C

C

C

C

C

B A A C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C H

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C A B C

C

C

C

C

C

C

C

C G

C

D

D

D A B D

D

C B C D

C

C

D

C B A C

C

C B C C

B B B D

C

C

C

A B A C

C C C D

B

C

C C B C

B

C C C C

C

C C B C

D C C C

C

C

B

C B B C

C

C

C

C

B

C B B C

C F

C B B D

C

B

C

B

C

B

C

B

C

C A A B

C B B C

C

C

C A B C

C B B C

B B B C

C C B C

A B A B

C B A C

C B B C

C

C

C

C

C

B

B

C

C

B

B

B

B

C

C

B

C

B

D

B

C

B

C

B

D

D H

B C B C

A

C C B D

A

C B B D

B

C B C B

C G

C

B

C

0

A

C B C D

B

B B B C

C C B C

A

A

A

A

B

A

B

B

B

A

A

A

A

A

A

B

B B B C

C

B

C

C

B

C C C C

C B C D G

C B C C

C B D C

C B C B

C D B D

C

C

C C B D

B

C B D C

B

C

A

A

B B C

B B A C C C

B

C B C C

B

B

B

A

C

C B C C C D

B B B C C C F

C C B B

B

A

C C B C C C G

C B A B

B

C

B

A C C

B

B B A B

B

B

C

B

B

B

A

B C C

B

B

D D D F

B

B

B

B

C B D B

B A A

C

B C C G

B

B

B

B B B B

B B A B

C C C C

A

B A B

C C C C

A B C

B B C

0 B B

A B B

A B B

A A B

A A A

A C C

0 A A

B C D

0 B B

A B B

0 C C

0 A A

0 A B

B C C

C B B

D C B C D D G

B C D

D B B B D D

A B B

B D D

A B C

C C D F

B B B

B B C C D D G

A B C

B C C

B C D

C B B B C D F

A D D

B C D

B C D

A C C

B C C

0 C C

A A B

0 B B

0 B C

A A A

A B B

0 B A

A B C

A B B

A C C

A A B

A B C

A B B

A A B

0 B C

A C C

A A B

0 B C

A C C

A D D

D B B B D D F

C B C C D D F

B A B

A C C

C C C F

C C D F

A B C

B C D

A D D

C C D D D D G

A

A

A

A

B

A

B

B

A

A

B

A

B

A

A

A

B B B A

A A A

B B C C C C

C C B C C C

C C C C D D

C C C

C C C

C C C

B B B

A B A B B C

A A A

C A B C C C

B A A

C B B D D D

C C C C C C

D C C D D D

C C C C C C

C C D

B C C

C C C

D B C D D D

C C B C C C

C C C

B B A B A B

B B B C B C

C C C C C C

D B C C C C

C C B B B B

B B B

B A B

C C C

C B C C C C

B B B C C C

B B B C C D

B A B B C B

C B A B B C

C A D C C C

B A B

B B B

C B C C C C

C C C

C C C

B B B

C B C C C C

B A A

C B B B B B

C B B C C C

D B C B A A

C B B B B C

C B B C B B

C C A B B B

C B C C C C

C C C C C C

B B B

C B C C C C

C C C C C C

C C B C C C

B B B

C B B C C C

C C C C C C

B B B B B B

D B D C C C

B B B

C B D C C C

D B C C C D

C B C C C C

C B C C D C

B A B

B B A

B B C

B B B

B B C A C B

A B B

A C C

C A A B C C E

C C B C C C E

C B C B C C F

C B B B B C

C C C F

A B B

C B A C B B

B C C

C C C E

D

C

C

C

C

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

B

B

B

B

A

B

B

A

A

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

B

C

B

B

C

B

B

A

B

A

A

B

B

B

A

B

B

B

B

B

B

B

B

B

B

A

B

A

C

B

B

A

B

B

B

B

A

B

B

B

A

A

B

B

B

B

A

B

A

B

B

B

B

A

A

B

A

B

B

A

B

B

B

A

B

A

B

A

B

B

C

B

B

B

B

B

B

B

B

B

A

B

B

B

B

B

B

B

A

B

A

A

B

A

A

B

B

B

B

B

B

B

A

C

C

B

B

B

C

B

B

B

C

B

B

B

A

A

B

A

A

A

B

A

C

C

B

B

B

B

B

B

B

B

C

A

C

B

A

B

A

B

B

B

B

B

B

A

B

B

B

A

C

B

A

B

A

B

A

B

B

B

A

B

C

B

C

C

B

C

A

B

B

B

B

C

B

B B C

B A B

A A A

A A A

A 0 A

B B B

C B B B C C

C D B C D C

B B B C C D

B B B C C C

C C C

C C C

B B C

B A A C C C

B C C

C D D

C B B C C C

A 0 A

A B A C C D

C C B C D C

B B B

C C C

B B B

C B B

C C C

C C C C C C

B C C

A 0 0

A A 0

A A 0

D C C D D D

C B B C C D

C B B C C D

C B B C C C

C C B C C D

C B A C B C

B B C C C D

C C D

B B C

C C C

D C B C C D

A A B

A A B

C C D

C B B C C C

A A A

B C C

C C B C C C

B A A C C C

B B C

C C B C C D

D C C D D D

C B C C C D

C A A C C D

C C C C C C

B B B

C B B B A B

B C C

A B 0

B C C

B B A

0 A 0

A B 0

B C C

C C B C C C

B C B B B C

A A A

A A A

C C C D C D

B B A B A B

A A A

B B A B C C

B C A C D D

D C A C C C

A A A

A A A

C C C C D C

C C B C C C

C C B C B C

B C B C B C

A A 0

A A A

0 A A

0 A 0

0 A 0

C D C

0 0 C

0 A A

A A A

B A B

A 0 0

0 A A

B B C

0 A 0

A B C

D B B C D C

C C A C D C

A A A

A A A

C B C C B B

C B C C B B

A A A

B A B

C B A

C B C

C C C

B A B

A A A

C C C

C A B

A 0 B

B B C

0 A A

C C C

A B B

A A A

A B 0

C B B

B B A

A A A

C C D

B B C

C C C

B B C

B A B

C B C

0 0 A

B B B

C B C

0 A 0

0 0 A

A A A

B B B

C C B

C B C

B A A

B A B

A A A

A A A

A A A

B A B

C A B

B B C

A B B

B A B

A B B

B B C

B B B

C A B

B A B

D B B

C B B

C B B

B B B

B A A

B B B

B 0 B

A B A

A A 0

A A A

B B C A = 1-25% inhibition, B = 25-50% inhibition, C = 51-75%inhibition, D = 76-100% inhibition. E = >30 μM IC₅₀, F = 11-30 μM IC₅₀,G = 5-10 μM IC₅₀, H = <5 μM IC₅₀.

Example 6 Rac and Rho Inhibition Assay

By substituting KRas G12D mutant protein with either Rac-1 or Rho-Aunder the assay conditions described in Example 5, Rac-1 and Rho-Ainhibition, respectively, were each determined.

Table 8 shows inhibition data for selected compounds tested in thescreening assays described above.

TABLE 8 % Inhibition at 20 μM of KRas G12D mutant, Rac-1 and Rho-Aprotein KRas KRas G12D G12D Q61H Rac-1 Rho-A Structure % Inh. % Inh. %Inh. % Inh.

C C D D

B C D D

B C C

B C D D

C C D C

B D D

D D D

B B A

B D D

B B B

A C C

B C C

0 B B

A C B

A C C

A C B

A B B

A C B

0 D C

B D D

0 C C

A C C

0 C C

0 B B

0 A B

B D C

C D C

D C D D

B C D

D B D D

A C B

B D D

A B C

C D D

B B B

B C C D

A A C

B D D

B A D

C B D D

A D D

B D D

B D D

A D D

B D D

0 D C

A C B

0 D C

0 C B

A B B

A C C

0 B B

A D C

A C C

A D C

A C C

A D C

A D C

A C C

0 D C

A D C

A C C

0 D C

A D C

A D D

D B D D

C C D D

B B B

A D D

C D D

C D D

A D C

B D D

A D D

C D D D

A A A

B C D D

C C D D

C C D D

C D C

C D D

C C C

B C C

A B D D

A B B

C C D D

B B B

C D D D

C C C D

D D D D

C C D D

C D D

B D D

C C C

D D D D

C C D D

C C C

B B B C

B C C C

C C D D

D C D D

C B D C

B B A

B C C

C C C

C C D D

B C C C

B C D D

B B C C

C B C B

C C D C

B C D

B B B

C C D D

C C C

C C C

B C C

C C D D

B C B

C B D C

C C C C

D B C C

C B C B

C C C C

C B D C

C C D D

C C D C

B B A

C C D C

C C D C

C C D D

B C B

C C D D

C C C C

B B C C

D C D D

B C C

C C D D

D C D D

C C D D

C C D D

B C C

B B B

B C C

B C C

B A C C

A B B

A C C

C B C C

C C C C

C B C D

C B B C

C C D

A B B

C C C C

B C C

C C D

B C C

B B C

A A A

A B A

A A B

B C B

C B C B

C C D D

0 0 A

B C D C

B C D C

C D D

C D D

B C C

B C D C

B C C

C D D

C C D D

A A A

C D D

C C D D

B A B

C C D

B B C

C B C

C C C D

C C C C

B C D

A 0 0

A A A

A A 0

D D D D

C C D D

C C D D

C C D D

C C D D

C C C B

C C D D

C D D

B C C

C C C

D C D D

A A A

A A A

C D D

C C D D

A A 0

B D D

C C C C

B C D D

B B C

D D D D

C C D D

C C D D

C C D D

B B C

C B C C

B D D

A A A

B C C

B B C

0 A A

A 0 A

B D D

C C D D

B B C C

A 0 0

A A A

C D D D

B B B C

A B B

B B C D

B C C D

D C D C

A A A

A B B

C C D D

C C C C

C C D D

B C C C

A A A

A A A

0 0 0

0 0 0

0 A 0

C D D

0 D C

0 A B

A B B

B C B

A A 0

0 B A

B B B

0 A 0

A C C

D C C D

C C C C

A 0 A

A 0 B

C C B C

C C B C

A 0 A

B A B

C D A

C B B

C B B

B B B

A B B

C B C

C B 0

A A B

B A A

0 A A

C C C

A B A

A A A

A A A

C C C

B B B

A 0 B

C C C

B C C

C C C

B C C

B A C

C C C

0 0 A

B C C

C D C

0 0 0

0 A 0

A A A

B B C

C C C

C D D

B B A

B C B

A B 0

A B A

A A 0

B C C

C C B

B B B

A B B

B B B

A A A

B C C

B C B

C C B

B C B

D C C

C C C

C C B

B C C

B C B

B C C

B B C

A B B

A A B

A A A

B B C A = 1-25% inhibition, B = 25-50% inhibition, C = 51-75%inhibition, D = 76-100% inhibition

Example 7

Compound 4 was prepared as described in Scheme 1. To a suspension ofcompound 4 (0.020 g, 0.088 mmol in dry acetonitrile (2 mL) a solution of10% HCl in dry dioxane was added dropwise until pH 3. After standing for0.5 h the solvents were removed in vacuum to obtain 0.023 g (0.088 mmol,100%) of target compound.

Example 8

The target compound was prepared from compound 4 in Scheme 1, accordingto the procedure for amide synthesis described in Step D, Scheme 1.

Example 9

To a solution of compound 4 from Scheme 1 (0.150 g, 0.66 mmol) inacetonitrile, [(4-methoxybenzyl)oxy]acetic acid (0.129 g, 0.66 mmol),DIPEA (0.46 mL, 2.64 mmol), and DMAP (0.005 g, 0.04 mmol) were added.Then TBTU (0.847 g, 2.64 mmol) was added, the resulting mixture wasrefluxed for 8 hours, and evaporated under reduced pressure. The residuewas purified by HPLC to yield the target amide.

Example 10

The target compound was prepared from compound 4 in Scheme 1, accordingto the procedure for amide synthesis described in Step D, Scheme 1.

Example 11

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step D, Scheme1.

Example 12

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step D, Scheme1.

Example 13

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step D, Scheme1.

Example 14

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 15

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 16

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 17

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step C, Scheme1.

Example 18

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step C, Scheme1.

Example 19

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure described in Step E, Scheme 1.

Example 20

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 21

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 22

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 23

The target compound was prepared from compound 4 in Scheme 1, accordingto the general procedure for amide synthesis described in Step E, Scheme1.

Example 24

The target compound, compound 8 in Scheme 2, was prepared according tothe procedure described in Scheme 2.

Example 25

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 26

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 27

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 28

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 29

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 30

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 31

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 32

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 32

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 34

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 35

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 36

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 37

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 38

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 39

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 40

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 41

The target compound was prepared from compound 10 in Scheme 2, accordingto the general procedure for amide synthesis described in Step E, Scheme2.

Example 42

The target compound, compound 13 in Scheme 3, was prepared according tothe procedure described in Scheme 3.

Example 43

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 44

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 45

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 46

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 47

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 48

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 49

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 50

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 51

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 52

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 53

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 54

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 55

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 56

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 57

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 58

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 59

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 60

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 61

The target compound was prepared from compound 8 in Scheme 4, accordingto the procedure described in Scheme 4.

Example 62

The target compound was prepared from compound 8 in Scheme 4, accordingto the procedure described in Scheme 4.

Example 63

The target compound was prepared from compound 13 in Scheme 4, accordingto the procedure described in Scheme 4.

Example 64

The target compound was prepared from compound 13 in Scheme 4, accordingto the procedure described in Scheme 4.

Example 65

Step A: To a solution compound 5 of Scheme 2 (30 g, 0.19 mol) in 300 mLdioxane HCl was added compound 11 (23.85 g, 0.23 mol). The reactionmixture was stirred at rt overnight, diluted dioxane (300 mL), refluxedfor 3 h, cooled and evaporated. The resulting residue was washed bymixture EtOAc-iPrOH (1:2). The yield of 12 was 36 g (0.157 mol, 83%).

Step B: To a solution compound 12 (36 g, 0.157 mol) in 650 mL aceticacid, bromine (35 mL) was added at rt. The reaction mixture was refluxed48 h, cooled, evaporated, diluted with water. The resulting precipitatewas filtered, washed with water and dried. The yield of 13 was 45 g(0.146 mol, 93%)

Step C: The compound 13 (40 g, 0.13 mol, 1 eq.) and phosphoryl chloride(300 mL) were heated at reflux for 24 h. The reaction mixture was thenevaporated to dryness. The crude residue was dissolved in CH₂Cl₂ andwashed carefully with ice-water and 5% NaHCO₃ solution. Organic layerwas dried over Na₂SO₄ and evaporated to dryness giving sufficiently purecompound 82 as yellowish powder (40 g, yield 95%).

Step D: Sodium (2.8 g, 0.122 mol, 2 eq) was added in portions tomethanol (400 mL). Once all the sodium metal had disappeared, 82 (20 g,0.061 mol, 1 eq) was added and the mixture was stirred at ambienttemperature overnight. The mixture was diluted with water and extractedwith diethyl ether. The organic layer was washed with water, brine,dried (Na₂SO₄), filtered and the solvent was removed under reducedpressure to give 83 (15.86 g, yield 81%) as an orange solid, which wasused in next step without purification.

Step E: Into a 500 mL flask were charged 83 (1 g, 3.10 mmol, 1 eq.),[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.127 g, 0.15 mmol, 0.05 eq.), cuprous iodide (0.057 g, 0.30mmol, 0.1 eq.), and THF (50 mL). The resulting mixture was degassed withalternating vacuum/nitrogen purges. The filtered 2-pyridylzinc bromidesolution (9.30 mmol, prepared as described in Org. Lett., 2015, 17,3170-3173) was then added. The mixture was degassed one more time andthen heated at reflux for 24 h. The reaction mixture was then cooled to20° C. and treated with MTBE (methyl tert-butyl ether, 130 mL) and 1 Nammonium chloride (130 mL). The mixture was stirred at 20-30° C. for 30min and then filtered. The lower aqueous layer was drawn off, and theremaining organic layer was treated with saturated aqueous NH₄Cl (50 mL)and stirred for 30 min. After settling, the lower aqueous layer wasremoved and the organic layer was collected. The resulting organicsolution was then filtered through a small pad of SiO₂. The SiO₂ pad waswashed with MTBE (25 mL). The solvent was evaporated, and the residuewas purified by HPLC to give the target compound (0.01 g, 0.031 mmol, 1%yield of 84).

Step F: A solution of 84 (0.01 g, 0.031 mmol) in HOAc (0.2 mL) and 48%aq. HBr (0.2 mL) was warmed to 65° C. for 3 h, and then cooled to rt.The resulting solution was concentrated to dryness and the residue wassuspended in EtOAc. The solid was filtered, washed with EtOAc (2 mL),dried to afford the target compound (0.101 g, 70% yield) as adihydrobromide salt.

Step G: The compound 83 (1 g, 3.1 mmol, 1 eq.) was dissolved in THF andthe solution was cooled to −78*° C., then 1.5 ml of nBuLi (1.2 eq.) wasadded dropwise and the resulting mixture was stirred for 20-30 minutesthen, 0.823 ml (4.034 mmol, 1.3 eq.) of borolane was added and thereaction mixture was warmed up to rt. The reaction mixture was quenchedwith aq. sol. of NH₄Cl and extracted with EA (3×30 ml), combinedorganics were dried over Na₂SO₄ and concentrated under vacuo to givecompound 85 as a brown oil, which was used in next step withoutpurification.

Step H: 0.3 g (1.56 mmol, 1 eq.) of 2-bromo-pyridine was mixed withcompound 85 (1.66 mmol, 1.05 eq.) in dioxane with 0.992 g (7.18 mmol) ofK₂CO₃ (25% aq. solution) and 0.02 mmol (0.026 g) of Pd(dppf)Cl₂ under Aratmosphere for 12 h. Then the reaction was mixed with water, extractedwith ethyl acetate (3×30 ml), the combined organics were dried overNa₂SO₄ and concentrated in vacuo to give the product as a brown oil. Thetarget compound 84 was isolated using HPLC (ACN/H₂O as a mobile phase),0.155 g. Yield 31%

Step I: 0.05 g of compound 84 was stirred at 100° C. in conc. HCl for 2day, and then the target compound was precipitated and isolated byfiltration. Yield 42.4%.

Example 66

Step A: 0.27 g (1.56 mmol, 1 eq.) of 2-bromo-6-aminopyridine 86 wasmixed with compound 85, prepared in Step G, Example 65 (1.66 mmol, 1.05eq.) in dioxane with 0.992 g (7.18 mmol) of K₂CO₃ (25% aq. solution) and0.02 mmol (0.026 g) of Pd(dppf)Cl₂ under an argon atmosphere for 12 h.Then the reaction was mixed with water, extracted with ethyl acetate(3×30 ml), and the combined organics were dried over Na₂SO₄ andconcentrated under vacuo to give compound 87 as a brown oil. Compound 87was isolated using HPLC (ACN/H₂O as a mobile phase), 0.158 g. Yield 30%

Step B: 0.158 g of compound 87 was stirred at 100*° C. in conc. HCl for2 days, then the target compound was precipitated and isolated byfiltration. Yield 53.8%.

Example 67

Step A: 0.3 g (1.56 mmol, 1 eq.) of 2-bromo-6-methoxypyridine 88 wasmixed with compound 85 (1.66 mmol, 1.05 eq.) in dioxane with 0.992 g(7.18 mmol) of K₂CO₃ (25% aq. solution) and 0.02 mmol (0.026 g) ofPd(dppf)Cl₂ under an argon atmosphere for 12 h. Then the reaction wasmixed with water, extracted with ethyl acetate (3×30 ml), and thecombined organics were dried over Na₂SO₄ and concentrated in vacuo togive compound 89 as a brown oil. Compound 89 was isolated using HPLC(ACN/H₂O as a mobile phase), 0.183 g. Yield 33%.

Step B: 0.05 g of compound 89 was stirred at 100*° C. in conc. HCl for 2days, and then the target compound was precipitated and isolated byfiltration. Yield 38.4%.

Example 68

The target compound was prepared in Step D, Scheme 10 (compound 43).

Example 69

The target compound was prepared in Step D, Scheme 10 (compound 44).

Example 70

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 71

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 72

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 73

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 74

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 75

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 76

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 77

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 78

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 79

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 80

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 81

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 82

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 83

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 84

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 85

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 86

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 87

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 88

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 89

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 90

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 91

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 92

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 93

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 94

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using morpholine as the amine in Step E, and the appropriate amine inStep G.

Example 95

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using N-methyl piperazine as the amine in Step E, and the appropriateamine in Step G.

Example 96

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using N-methyl piperazine as the amine in Step E, and the appropriateamine in Step G.

Example 97

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using N-methyl piperazine as the amine in Step E, and the appropriateamine in Step G.

Example 98

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using bis(2-methoxyethyl)amine as the amine in Step E, and theappropriate amine in Step G.

Example 99

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using bis(2-methoxyethyl)amine as the amine in Step E, and theappropriate amine in Step G.

Example 100

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G andusing bis(2-methoxyethyl)amine as the amine in Step E, and theappropriate amine in Step G.

Example 101

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G,using thiomorpholine 1,1-dioxide as the amine in Step E, and theappropriate amine in Step G.

Example 102

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G andusing thiomorpholine 1,1-dioxide as the amine in Step E, and theappropriate amine in Step G.

Example 103

The target compound was prepared from compound 20 in Scheme 5, accordingto the general procedures described in Scheme 5 for Steps E, F and G andusing thiomorpholine 1,1-dioxide as the amine in Step E, and theappropriate amine in Step G.

Example 104

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 105

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 106

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 107

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 108

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 109

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 110

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 111

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 112

The target compound was prepared from compound 25 in Scheme 6, accordingto the procedure for amide synthesis described in Step B, Scheme 6.

Example 113

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 114

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 115

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 116

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 117

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 118

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 119

The target compound was prepared from compound 30 in Scheme 7, accordingto the procedure for amide synthesis described in Step E, Scheme 7.

Example 120

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 121

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 122

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 123

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 124

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 125

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 126

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 127

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 128

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 129

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 130

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 131

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 132

Step A: The compound 18, prepared as described in Scheme 5, (40 g, 0.13mol, 1 eq.) and phosphoryl chloride (300 mL) were heated at reflux for24 h. The reaction mixture was then evaporated to dryness. The cruderesidue was dissolved in CH₂Cl₂ and washed carefully with ice-water and5% NaHCO₃ solution. The organic layer was dried over Na₂SO₄ andevaporated to dryness giving sufficiently pure compound 90 as yellowishpowder (40 g, yield 95%).

Step B: To a stirred solution of 90 (10 g, 0.031 mol, 1 eq) in MeOH (100mL), was added morpholine (8.1 g, 0.993 mol, 3 eq) and the reaction leftto stir at reflux for 5 hours. The reaction mixture was diluted withwater and extracted with CHCl₃. Organic layer was evaporated underreduced pressure to give crude product. The crude material was purifiedby column chromatography using CHCl₃:MeCN (1:4) as eluent to affordcompound 91 (9.25 g, 0.024 mol, 80% yield).

Step C: The mixture of compound 91 (9 g, 0.023 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (200 ml) was stirredovernight under CO (10 bar) in autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield of 92 was 6.55 g (0.0184 mol, 80% yield).

Step D: Compound 92 was added to a 1M solution of NaOH in methanol. Thereaction mixture was heated at reflux overnight and evaporated. Thesolid residue was dissolved in water and acidified by 3N HCl to pH ˜4-5.The precipitate being formed was filtered and washed with water anddried in vacuo to give 93.

Step E: To a solution of 93 (1 g, 2.93 mmol, 1 eq.) in DMF (10 mL) wasadded carbonyldiimidazole (CDI, CAS 530-62-1) (0.568 g, 3.51 mmol, 1.2eq.). The resultant solution was stirred at room temperature for 1 h andmixed with aqueous ammonium (25%). The mixture was diluted with waterand precipitate was filtered and air dried to give compound 94 as awhite solid (0.9 g, 2.63 mmol, 90% yield).

Step F: Trifluoroacetic anhydride (0.46 g, 2.19 mmol, 1.5 eq.) was addedvia syringe to a stirring solution of compound 94 (0.5 g, 1.46 mmol, 1eq.) and triethylamine (0.612 mL, 4.39 mmol, 3 eq.) in dichloromethaneat 5° C. The cooling bath was removed, the resulting solution was warmedto room temperature and stirred for 16 hours. The mixture wasconcentrated in vacuo. Water was added to the residue and the productwas extracted with dichloromethane (3×70 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated todryness. The product was purified by flash chromatography on silica toobtain the target compound as a light yellow solid (0.435 g, 1.348 mmol,92% yield).

Example 133

In a 1 L round bottom flask compound 17, prepared as described in StepA, Scheme 5 (10 g, 43.6 mmol), was taken up in acetic acid (500 mL) andNCS (6.95 g, 52.3 mmol, 1.2 eq.) was added. The reaction was heated at60° C. for 6 hours. The reaction was then cooled to room temperature andquenched with water. The precipitate being formed was filtered and driedto give the target compound as a grey powder (9.3 g, 35.3 mmol, 81%yield).

Example 134

Step A: The compound 95 (Example 133) (20 g, 0.076 mol, 1 eq) andphosphoryl chloride (400 mL) were heated at reflux for 24 h. Thereaction mixture was then evaporated to dryness. The crude residue wasdissolved in CH₂Cl₂ and washed carefully with ice-water and 5% NaHCO₃solution. Organic layer was dried over Na₂SO₄ and evaporated to drynessgiving sufficiently pure compound 96 as yellowish powder (19.2 g, yield90%).

Step C: To a stirred solution of 96 (1 g, 3.558 mol, 1 eq) in MeOH (30mL), was added morpholine (0.93 g, 10.67 mmol, 3 eq) and the reactionleft to stir at reflux for 5 hours. The reaction mixture was dilutedwith water and extracted with CHCl₃. The organic layer was evaporatedunder reduced pressure to give the crude product. The crude material waspurified by column chromatography using CHCl₃: MeCN (1:4) as eluent toafford the target compound (0.896 g, 2.70 mmol, 76% yield).

Example 135

Step A: Compound 97 (10 g, 41.8 mmol, 1.0 eq) andpyridine-2-carbonitrile 11 (5.22 g, 50.16 mmol, 1.2 eq) were mixed inMeOH (150 mL). The mixture was cooled to 0° C., and sodium methoxide(6.77 g, 125.4 mmol, 3 eq) was added. The reaction mixture was stirredat reflux for 48 h, cooled to r.t, diluted with water, acidified by AcOHand extracted by EtOAc 3 times. The organic layer was evaporated underreduced pressure. Residue was purified by column chromatography to givethe target compound as a light yellow solid (2.2 g, yield—17.7%).

Example 136

Step A: The compound 98 (Example 135) (2.0 g, 6.72 mmol, 1 eq.) andphosphoryl chloride (30 mL) were heated at reflux for 24 h. The reactionmixture was then evaporated to dryness. The crude residue was dissolvedin CH₂Cl₂ and washed carefully with ice-water and 5% NaHCO₃ solution.Organic layer was dried over Na₂SO₄ and evaporated to dryness givingsufficiently pure compound 99 as grey powder (2.01 g, yield 95%).

Step B: To a stirred solution of compound 99 (1.5 g, 4.76 mmol) in MeOH,was added morpholine (1.24 g, 14.28 mmol, 3 eq.) and the reaction leftto stir at reflux for 5 hours. The reaction mixture was diluted withwater and extracted with CHCl₃. The organic layer was evaporated underreduced pressure to give crude product. The crude material was purifiedby column chromatography using CHCl₃: MeCN (10-30 percent) as eluent toafford the target compound as a white solid (1.25 g, yield 72%).

Example 137

Steps A and B: Compound 100 (1,202 g, 8.68 mmol, 1.0 eq) was added tothe cooled (0° C.) solution of sodium methoxide (0,516 g, 9.55 mmol, 1.1eq) in methanol (20 mL). The reaction mixture was stirred at roomtemperature for 2 h to give 101, then cooled to 0° C. Compound 16 (1,364g, 8.68 mmol, 1.0 eq) and sodium methoxide (0,516 g, 9.55 mmol, 1.1 eq)were added to the resulting mixture at 0° C. The reaction mixture wasstirred at reflux for 16-18 h (monitored by TCL), cooled andconcentrated in vacuo. The residue was diluted with water (30 mL),acidified by 5% HCl to pH=7 and extracted with CH₂Cl₂ (2×50 mL). Theorganic layer was washed with water, saturated sodium chloride, driedover Na₂SO₄, filtered and concentrated in vacuo. The solids weretriturated with MTBE to give the target compound (1.1 g, 49% yield).

Example 138

The compound 102 (Example 137) (1.38 g, 5.32 mmol) and NaOAc (0.873 g,10.64 mmol) were dissolved in acetic acid (10 mL). To this mixture Br2(0.936 g, 5.86 mmol) was added. The resulting mixture was stirred at 80°C. for 16-18 h. Then the reaction mixture was cooled and evaporated todryness. The residue was precipitated by water (50 mL), filtered, washedsequentially with isopropyl alcohol, hexanes and dried in vacuo to give1.2 g of the target compound as a yellowish powder (67% yield).

Example 139

The mixture of 103 (Example 138) (0.3 g, 0.88 mmol) and CuCN (0.236 g,2.64 mmol) was stirred at 150° C. for 3 h. The reaction mixture wascooled to room temperature, diluted with aqueous ammonia solution 25%(20 mL) and extracted with CH₂Cl₂ (2×50 mL). The organic layer waswashed with water, dried over Na₂SO₄ and evaporated to dryness. Theresidue was purified by HPLC to give the target compound (11 mg, 67%yield).

Example 140

Step A: 1,3-Dioxo-1,3dihydro-isoindol-2-yl)-acetonitrile 104 (20 g,106.8 mmol) was dissolved in 4N HCl in dioxane (200 mL). The mixture wasstirred at room temperature, and MeOH (20 mL) was added. The solutionturned cloudy shortly. The precipitate was collected and washed withether to provide 18 g (66%) of 105.

Step B: A suspension of 105 (18 g, 70.7 mmol) in MeOH (270 mL) was addedto a saturated NH₃/MeOH solution. The mixture was stirred at 0° C. andthen was allowed to warm to room temperature. After all the volatileswere removed, the product 106 was used in the next step without furtherpurification.

Step C: Compound 106 (16.95 g, 70.7 mmol) and the sodium salt of3-hydroxy-2-methoxy-acrylic acid methyl ester 107 (13.07 g, 84.84 mmol)were mixed in MeOH (500 mL) and stirred at room temperature for 2 h, andthen heated at reflux overnight. The crude mixture was filtered. Afterthe filtrate was concentrated, the resulting residue was purified bycolumn chromatography affording 1 g (5% yield) of 108.

Step D: Hydrazine (4 mL) was added to a suspension of 108 (0.5 g, 1.75mmol) in EtOH (15 mL), and the mixture was stirred. The completion ofreaction was monitored by TCL. The precipitate was filtered and thefiltrate was purified by column chromatography to afford 10 mg (4%yield) of the target compound.

Example 141

Step A: Lithium hydroxide (0.025 g, 0.6 mmol) was added to a solution of37, prepared as described in Scheme 9 (0.14 g, 0.4 mmol) in THF/water(1:1, 20 mL). The reaction mixture was allowed to stir at roomtemperature overnight. The reaction mixture was concentrated andresidue, compound 109, was directly used in the next step withoutfurther purification.

Step B: HATU (CAS [148893-10-1], 0.168 g, 0.44 mmol, 0.1 eq.), DIPEA andcompound 110 (Example 140) were added sequentially to a solution of thelithium salt 109 (0.139 g, 0.4 mmol) in DMF (20 mL). The reactionmixture was allowed to stir at room temperature overnight. The reactionmixture was concentrated in vacuo. The residue was purified by HPLCaffording the target compound (0.01 g, 5% yield).

Example 142

A suspension of 37, prepared as described in Step C, Scheme 9 (0.07 g,0.2 mmol) in MeOH (5 mL) was added to a saturated NH₃/MeOH solution. Themixture was stirred 12 h at room temperature. The precipitate wascollected and washed with ether to provide 0.01 g (15% yield) of thetarget compound.

Example 143

Step A: Into a 500 mL flask were charged 13 (1 g, 3.25 mmol, 1 eq.),[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.132 g, 0.16 mmol, 0.05 eq.), cuprous iodide (0.061 g, 0.32mmol, 0.1 eq.), and THF (50 mL). The resulting mixture was degassed withalternating vacuum/nitrogen purges. The filtered 4-piperidylzinc iodidesolution 111 (9.75 mmol, prepared as described in J. Org. Chem. 2004,69, 5120-5123) was then added. The mixture was degassed one more timeand then heated at reflux for 24 h. The reaction mixture was then cooledto 20° C. and treated with MTBE (methyl tert-butyl ether, 130 mL) and 1N ammonium chloride (130 mL). The mixture was stirred at 20-30° C. for30 min and then filtered. The lower aqueous layer was drawn off, and theremaining organic layer was treated with saturated aqueous NH₄Cl (50 mL)and stirred for 30 min. After settling, the lower aqueous layer wasremoved and the organic layer was collected. The resulting organicsolution was then filtered through a small pad of SiO₂. The SiO₂ pad waswashed with MTBE (25 mL). The solvent was evaporated, and the residuewas purified by HPLC (0.202 g, 0.49 mmol, 15% yield of 112).

Step B: The mixture of 112 (0.1 g, 0.243 mmol) and 6N aqueous HCl (5 ml)was stirred at 50° C. for 5 h. The resulting solution was evaporated todryness. The residue was triturated with dioxane and dried in vacuo togive the target compound. The yield was 80% (0.84 g, 0.242 mmol).

Example 144

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 145

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 146

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 147

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 148

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 149

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 150

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 151

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 152

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 153

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 154

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 155

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 156

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 157

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 158

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 159

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 160

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 161

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 162

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 163

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 164

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 165

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 166

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 167

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 168

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 169

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 170

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 171

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 172

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 173

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 174

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 175

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 176

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 177

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 178

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3, and using amine 110 (Example 140).

Example 179

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 180

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 181

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 182

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 183

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 184

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 185

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 186

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 187

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 188

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 189

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 190

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 191

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 192

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 193

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 194

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 195

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 196

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 197

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 198

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 199

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 200

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 201

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 202

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 203

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 204

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 205

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 206

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 207

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 208

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 209

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 210

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 211

The target compound was prepared from compound 45, synthesized asdescribed in Step E, Scheme 10, using a procedure analogous to Step B,Scheme 8 for the preparation of compound 32.

Example 212

The target compound was prepared from compound 46, prepared as describedin Step E, Scheme 10, using a procedure analogous to Step B, Scheme 8for the preparation of compound 32.

Example 213

Reactions were conducted on a 100 mg scale. Compound 43, prepared asdescribed in Scheme 10, Step D (1 eq.), aryl boronic acid (1.5 eq.),K₂CO₃ (3 eq.) and [1,1′bis(oliphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. The organic layer was evaporated and dried in vacuo. The residuewas purified by HPLC to afford the title compounds (Yields: 30-40%).

Example 214

Reactions were conducted on a 100 mg scale. Compound 43, prepared asdescribed in Scheme 10, Step D (1 eq.), aryl boronic acid (1.5 eq.),K₂CO₃ (3 eq.) and[1,1′bis(oliphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. The organic layer was evaporated and dried in vacuo. The residuewas purified by HPLC to afford the title compounds (Yields: 30-40%).

Example 215

Reactions were conducted on a 100 mg scale. Compound 44, prepared asdescribed in Scheme 10, Step D (1 eq.), aryl boronic acid (1.5 eq.),K₂CO₃ (3 eq.) and[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. The organic layer was evaporated and dried in vacuo. The residuewas purified by HPLC to afford the title compounds (Yields: 30-40%).

Example 216

The target compound was prepared from compound 113, using a procedureanalogous to Step B, Scheme 8 for the preparation of compound 32.

Example 217

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 218

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 219

The target compound was prepared from compound 15 in Scheme 3, accordingto the general procedure for amide synthesis described in Step E, Scheme3.

Example 220

The target compound was prepared from compound 50 in Scheme 11,according to the general procedure for amide synthesis described in StepD, Scheme 11.

Example 221

The target compound was prepared from compound 50 in Scheme 11,according to the general procedure for amide synthesis described in StepD, Scheme 11.

Example 222

The target compound was prepared from compound 50 in Scheme 11,according to the general procedure for amide synthesis described in StepD, Scheme 11.

Example 223

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 224

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 225

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 226

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 227

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 228

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 229

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 230

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 231

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 232

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 233

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 234

Step A: Sodium (2.8 g, 0.122 mol, 2 eq) was added in portions to benzylalcohol solution (13.1 g, 0.122 mol 2 eq) if DMF (400 mL). Once all thesodium metal had disappeared, compound 41, prepared in Step C, Scheme 10(20 g, 0.061 mol, 1 eq) was added and the mixture was stirred at ambienttemperature overnight. The mixture was diluted with water and extractedwith diethyl ether. The organic layer was washed with water, brine,dried (Na₂SO₄), filtered and the solvent was removed under reducedpressure to give the title compound 114 (19.6 g, yield 81%) as an orangesolid, which was used in next step without purification.

Step B: A mixture of compound 114 (1 eq.), aryl boronic acid (1.5 eq.),K₂CO₃ (3 eq.) and[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. Organic layer was evaporated and dried in vacuo. The residue waspurified by HPLC to afford the compound 115 in 50% yield.

Step C: Compound 115 and Pd/C (10%) in methanol (200 mL) washydrogenated under 50 atm of hydrogen for 24 hr. Then, the mixture wasfiltered and the filtrate was evaporated to dryness to give the targetcompound in 90% yield (2 g scale).

Example 235

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 236

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 237

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 238

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 239

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 240

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 241

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 242

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 243

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 244

Step A: A mixture of compound 83 (prepared in Step D, Example 65) (5 g,1 eq.), (3-(trifluoromethyl)phenyl)boronic acid (4.44 g, 1.5 eq.), K₂CO₃(2.15 g, 3 eq.) and[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.623 g, 0.05 eq.) in a mixture of dioxane (300 ml) and H₂O(300 ml) was stirred overnight under argon atmosphere at 95° C. Aftercooling down to room temperature, the mixture was diluted with CH₂Cl₂,and washed with water. Organic layer was evaporated and dried in vacuo.The residue was purified by HPLC to afford 116 (1.3 g, 22% yield).

Step B: The compound 116 (1.3 g) was heated in aqueous 58% HBr solution(100 mL) at 100° C. for 24 hr. Then, the mixture was evaporated todryness and the product was precipitated with ethyl acetate to give thetarget compound as white solid (HBr, 1.4 g, 89%).

Example 245

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 246

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 247

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 248

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 249

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 250

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 251

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 252

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 253

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 254

Step A: Sodium (2.8 g, 0.122 mol, 2 eq) was added in portions to benzylalcohol solution (13.1 g, 0.122 mol 2 eq) if DMF (400 mL). Once all thesodium metal had disappeared, compound 41, prepared in Step C, Scheme 10(20 g, 0.061 mol, 1 eq) was added and the mixture was stirred at ambienttemperature overnight. The mixture was diluted with water and extractedwith diethyl ether. The organic layer was washed with water, brine,dried (Na₂SO₄), filtered and the solvent was removed under reducedpressure to give the title compound 117 (19.6 g, yield 81%) as an orangesolid, which was used in next step without purification.

Step B: A mixture of compound 117 (1 eq.), aryl boronic acid (1.5 eq.),K₂CO₃ (3 eq.) and[1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.05 eq.) in a mixture of dioxane (3 ml) and H₂O (1 ml) wasstirred overnight under argon atmosphere at 95° C. After cooling down toroom temperature, the mixture was diluted with CH₂Cl₂, and washed withwater. Organic layer was evaporated and dried in vacuo. The residue waspurified by HPLC to afford the target compound in 50% yield.

Step C: Compound 118 and Pd/C (10%) in methanol (200 mL) washydrogenated under 50 atm of hydrogen for 24 hr. Then, the mixture wasfiltered and the filtrate was evaporated to dryness to give the targetcompound in 90% yield (2 g scale).

Example 255

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 256

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 257

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 258

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 259

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 260

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 261

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 262

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 263

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 264

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 265

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 266

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 267

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 268

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 269

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 270

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 271

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 272

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 273

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 274

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 275

The target compound was prepared from compound 13 using the generalprocedure described in Scheme 12.

Example 276

The target compound was prepared from compound 40, prepared in Step B,Scheme 10, using the general procedure described in Scheme 12.

Example 277

The target compound was prepared from compound 40, prepared in Step B,Scheme 10, using the general procedure described in Scheme 12.

Example 278

The target compound was prepared from compound 40, prepared in Step B,Scheme 10, using the general procedure described in Scheme 12.

Example 279

The target compound was prepared from compound 40, prepared in Step B,Scheme 10, using the general procedure described in Scheme 12.

Example 280

The target compound was prepared in Step A, Scheme 5 (compound 17).

Example 281

The target compound was prepared in Step B, Scheme 5 (compound 18).

Example 282

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 283

The target compound was prepared from compound 32 in Scheme 8, accordingto the procedure for amide synthesis described in Step C, Scheme 8.

Example 284

Step A: To a solution compound 114 (0.5 g, 1.6 mmol) in DMF (5 mL) wasadded KO-tBu (0.1 g, 0.89 mmol) and picolinonitrile 11 (0.2 g, 1.92mmol). The reaction mixture was heated to 90° C. for 4 d andconcentrated under reduced pressure. The resulting mixture was dilutedwith water and extracted with EtOAc. The organic layer was dried overNa₂SO₄ and evaporated. The crude product was chromatographed on a silicsgel column to give compound 115. The yield was 18 mg (0.047 mmol, 3%).

Step B: Compound 115 (18 mg, 0.047 mmol) was dissolved in 5 mL 2Mmethanolic solution of HCl. The reaction mixture was stirred overnightand concentrated under reduced pressure. The resulting residue waswashed with Et₂O and dried. The yield of the target compound was 8 mg(0.025 mmol, 53%)

Example 285

Step A: To a solution compound 116 (0.5 g, 1.5 mmol) in DMF (5 mL) wasadded KO-tBu (0.1 g, 0.89 mmol) and picolinonitrile (0.2 g, 1.92 mmol).The reaction mixture was heated to 90° C. for 4 d and concentrated underreduced pressure. The resulting mixture was diluted with water andextracted with EtOAc. The organic layer was dried over Na₂SO₄ andevaporated. The crude product was chromatographed on a silica gelcolumn. The yield of compound 117 was 15 mg (0.038 mmol, 2.5%).

Step B: Compound 117 (15 mg, 0.038 mmol) was dissolved in 5 mL 2Mmethanolic solution of HCl. The reaction mixture was stirred overnightand concentrated under reduced pressure. The resulting residue waswashed with Et₂O and dried. The yield was 8 mg (0.024 mmol, 63%).

Example 286

Step A: Hexamethyldisilazane (8.11 mL, 0.038 mol, 1.5 eq) was addeddropwise to HOAc (7 mL). The resulting mixture was added to a suspensionof malononitrile 52 (2.78 mL, 0.05 mol, 2.0 eq) and compound 51 (5 g,0.025 mol, 5 g, 1.0 eq) in HOAc (5 mL). The reaction mixture was stirredwith reflux overnight then, allowed to cool down to RT and diluted withtoluene (30 mL) and water (20 mL). The organic layer was separated,washed with water (3*2 mL), dried over Na₂SO₄ and concentrated underreduced pressure affording compound 53 (4.75 g, 78% yield).

Step B: Sulphur (0.75, 0.023 mol, 1.2 eq) was added to a solution ofcompound 53 (4.75 g, 0.019 mol, 1.0 eq) in THF (20 mL). The resultingmixture was stirred at 50° C. for 30 min and then NaHCO₃ (1.64 g, 0.19mol, 1.0 eq) was added. Then, the reaction mixture was stirred at 50° C.overnight and diluted with EtOAc. The organic phase was dried withNa₂SO₄ and evaporated in vacuo to obtain compound 54 (3.39 g, 63%yield).

Step C: The compound 54 (3.93 g, 0.012 mol, 1.0 eq) and 80% H₂SO₄(10 mL)were stirred at RT for 18 h. After completion (monitored by LCMS), thereaction mixture was poured in ice and aqueous ammonia (5 mL) was added.The precipitate formed was filtered off, washed with water and air-driedto give compound 55. The yield was 2.35 g (65%).

Step D: Lithium 1-methyl-1H-imidazole-2-carboxylate 56 (1.32 g, 0.01mol, 1.3 eq), triethylamine (1.67 g, 0.01 mol, 1.4 eq) and1-methyl-1H-imidazole (1.64 g, 0.02 mol, 2.5 eq) were dissolved inCH₂Cl₂ (15 mL). The resulting mixture was cooled to 0° C. andmethanesulfonyl chloride (1.1 g, 9.6 mmol, 1.2 eq) was added dropwise.Then, the resulting suspension was stirred for 30 min and compound 55(2.35 g, 8.0 mmol, 1.0 eq) was added in one portion. The reactionmixture was stirred overnight and evaporated in vacuo. The residue wasdissolved in DMSO and potassium tert-butoxide (1.79 g, 0.016 mol, 2.0eq) was added. The resulting suspension was stirred overnight at 80° C.and HOAc (5 mL) was added. The resulting precipitate was filtered off,washed with water and dried to give compound 57. The yield was 2.34 g(76%).

Step E: The compound 57 (2.34 g, 6.1 mmol, 1.0 eq.) and phosphorylchloride (7 mL) were stirred at 90° c. for 18 h. The reaction mixturewas poured into ice and extracted with EtOAc. The organic layer wasdried (Na₂SO₄), filtered and the solvent was removed under reducedpressure to give compound 58 (1.98 g, 81%).

Step F: To a solution of compound 58 (1.98 g, 4.94 mmol, 1.0 eq) in DMSO(3 mL) 2-methoxyethanamine (0.37 g, 4.94 mmol, 1.0 eq) and DIPEA (0.83g, 6.42 mmol, 1.3 eq) were added. The resulting mixture was stirredovernight at 60° C. Then, the reaction suspension was poured into waterand extracted with EtOAc. The solvent was evaporated and the residue waspurified by HPLC to obtain the target compound (1.36 g, 63% yield).

Example 287

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.61 g, (80.5%); Step B 1.0 g(71.4%); Step C 342 mg (68%); Step D 155 mg (52%); Step E 136 mg (80%);Step F 48.3 mg (49%).

Example 288

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.72 g (86%); Step B 1.02 g (73%);Step C 371 mg (74%); Step D 167 mg (56%); Step E 143 mg (84%); Step F50.6 mg (51%).

Example 289

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.49 g (72.5%); Step B 0.81 g (57%);Step C 411 mg (82%); Step D 172 mg (57%); Step E 138 mg (81%); Step F51.7 mg (52%).

Example 290

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.79 g (89.5%); Step B 1.10 g (80%);Step C 0.393 g (78%); Step D 169 mg (56%); Step E 142 mg (83%); Step F18.3 mg (18%).

Example 291

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.66 g (83%); Step B 1.06 g (76%);Step C 0.366 g (73%); Step D 176 mg (59%); Step E 152 mg (89%); Step F11.1 mg (11%).

Example 292

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.73 g (86.5%); Step B 0.97 g(69.3%); Step C 0.331 g (66%); Step D 181 mg (60%); Step E 146 mg (86%);Step F 48.3 mg (48%).

Example 293

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.68 g (84%); Step B 1.11 g (79%);Step C 0.378 g (75%); Step D 159 mg (53%); Step E 151 mg (89%); Step F46.1 mg (46%).

Example 294

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.74 g (87%); Step B 1.07 g (76%);Step C 0.358 g (71%); Step D 179 mg (60%); Step E 149 mg (87%); Step F11.2 mg (11%).

Example 295

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.63 g (81.5%); Step B 0.89 g (63%);Step C 0.362 g (72%); Step D 177 mg (59%); Step E 137 mg (80%); Step F52.9 mg (53%).

Example 296

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.64 g (82%); Step B 1.01 g (72%);Step C 0.401 g (80%); Step D 164 mg (55%); Step E 131 mg (77%); Step F51.0 mg (51%).

Example 297

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.67 g (83.5%); Step B 0.98 g (70%);Step C 0.372 g (74%); Step D 185 mg (62%); Step E 147 mg (86%); Step F58.6 mg (59%).

Example 298

The target compound was prepared according to the procedure described inScheme 13. The yields were: Step A 1.76 g (88%); Step B 1.04 g (74%);Step C 0.369 g (74%); Step D 163 mg (54%); Step E 150 mg (88%); Step F24.4 mg (25%).

Example 299

The target compound was prepared according to the procedure described inScheme 14, using the conditions for Step C when R=4-methoxyphenyl. Theyields were: Step A 1.66 g (83%); Step B 1.21 g (81%); Step C 0.305 g(61%); Step D 176 mg (59%); Step E 149 mg (83%); Step F 97 mg (97%).

Example 300

The target compound was prepared according to the procedure described inScheme 14, using the conditions for Step C when R=2-chlorophenyl. Theyields were: Step A 1.73 g (86.5%); Step B 1.14 g (76%); Step C 0.365 g(73%); Step D 183 mg (61%); Step E 159 mg (88%); Step F 57.2 mg (52%).

Example 301

The target compound was prepared according to the procedure described inScheme 14, using the conditions for Step C when R=4-pyridinyl. Theyields were: Step A 1.68 g (84%); Step B 1.19 g (80%); Step C 0.35 g(70%); Step D 169 mg (56%); Step E 164 mg (91%); Step F 15 mg (15%).

Example 302

The target compound was prepared according to the procedure described inScheme 14, using the conditions for Step C when R=2-pyridinyl. Theyields were: Step A 1.59 g (79.5%); Step B 1.05 g (75%); Step C 0.37 g(74%); Step D 174 mg (58%); Step E 138 mg (77%); Step F 47.3 mg (47%).

Example 303

The target compound was prepared according to the procedure described inScheme 15, using the conditions for Step C when R=3-methoxyphenyl. Theyields were: Step A 1.65 g (82.5%); Step B 1.14 g (76%); Step C 0.365 g(73%); Step D 164 mg (55%); Step E 134 mg (78%); Step F 49.3 mg (50%).

Example 304

The target compound was prepared according to the procedure described inScheme 15, using the conditions for Step C when R=2-chlorophenyl. Theyields were: Step A 1.67 g (83.5%); Step B 1.07 g (71%); Step C 0.305 g(61%); Step D 179 mg (60%); Step E 147 mg (86%); Step F 56.5 mg (57%).

Example 305

The target compound was prepared according to the procedure described inScheme 16. The yields were: Step A 1.78 g (89%); 1.21 g (81%); Step C0.389 g (78%); Step D 159 mg (53%); Step E 141 mg (88%); Step F 94.0 mg(94%).

Example 306

The target compound was prepared according to the procedure described inScheme 16. The yields were: Step A 1.65 g (82.5%); Step B 1.26 g (84%);Step C 0.367 g (73%); Step D 173 mg (58%). Step E 134 mg (83%); Step F57.3 mg (57%).

Example 307

Step A: 2-Amino-5-methyl-4-phenylthiophene-3-carboxamide 123 (1.0 eq)was refluxed with 1-methylimidazole-2-carboxaldehyde (1.1 eq) in acetic(5 mL) acid for 24 h. After completion of the reaction (confirmed byTLC), solution was cooled and diluted with water. The precipitate wasfiltered off and dried to give compound 124 (Yield—87%) as a brownsolid. The scale was calculated on 700 mg theoretical yield of product.Yield: 595 mg (85%).

Step B: The compound 124 (1.0 eq) was added to phosphorous trichloride(3 mL) and the mixture was stirred with reflux for 12 h. Then thereaction mixture was poured into 25% ammonia solution in cold water (30ml) and stirred for 1 h. The target compound was extracted with DCM(2*40 ml), dried (Na₂SO₄) and the solvent removed in vacuo to give crudeproduct 125 as a brown solid. The reaction mixture was used in the nextstep without purification. The scale was calculated on a theoreticalyield of 1 g of product. Yield: 0.66 g (65%).

Step C: To a solution of compound 125 (1.0 eq) in chloroform (10 mL) wasadded triethylamine (1.5 eq) and then 2-methoxyethylamine (1.0 eq). Thereaction was stirred for an additional 24 hours at 60° C. After thecompletion of reaction (confirmed by TLC), the mixture was concentratedunder reduced pressure, poured into H₂O and extracted with EtOAc (2*40ml), dried (Na₂SO₄), the solvent removed in vacuo to give crude productx as a brown solid. The crude product was purified using HPLC (gradientH₂O/CH₃CN mixture) yielding 0.045 g of the target compound. The scalewas calculated based on a theoretical yield of 0.45 g of final compound.Yield: 0.045 g (11.2%).

Example 308

Step A: 2-Amino-5-methyl-4-phenylthiophene-3-carboxamide 123 (1.0 eq)was refluxed with 1-methylimidazole-4-carboxaldehyde (1.1 eq) in acetic(5 mL) acid for 24 h. After completion of the reaction (confirmed byTLC), solution was cooled and diluted with water. The precipitate wasfiltered off and dried to give compound 126 (Yield—87%) as a brownsolid. The scale was calculated on 700 mg theoretical yield of product.Yield: 609 mg (87%).

Step B: Compound 126 (1.0 eq) was added to phosphorous trichloride (3mL) and the mixture was stirred with reflux for 12 h. Then the reactionmixture was poured into 25% ammonia solution in cold water (30 ml) andstirred for 1 h. The target compound was extracted with DCM (2*40 ml),dried (Na₂SO₄) and the solvent removed in vacuo to give crude product127 as a brown solid. The reaction mixture was used in the next stepwithout purification. The scale was calculated on a theoretical yield of1 g of product. Yield: 0.47 g (47%).

Step C: To a solution of compound 127 (1.0 eq) in chloroform (10 mL) wasadded triethylamine (1.5 eq) and then 2-methoxyethylamine (1.0 eq). Thereaction was stirred for an additional 24 hours at 60° C. After thecompletion of reaction (confirmed by TLC), the mixture was concentratedunder reduced pressure, poured into H₂O and extracted with EtOAc (2*40ml), dried (Na₂SO₄), the solvent removed in vacuo to give crude productx as a brown solid. The crude product was purified using HPLC (gradientH₂O/CH₃CN mixture) yielding 0.25 g of the target compound. The scale wascalculated based on a theoretical yield of 0.45 g of final compound.Yield: 0.25 g (51.2%).

Example 309

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.82 g (82%). The yield after StepB was 0.23 g (46%). The yield of the target compound obtained from StepC was 152 mg (76%).

Example 310

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.63 g (63%). The yield after StepB was 0.25 g (50%). The yield of the target compound obtained from StepC was 31.5 mg (16%).

Example 311

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.77 g (57%). The yield after StepB was 0.33 g (66%). The yield of the target compound obtained from StepC was 31.3 mg (16%).

Example 312

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.86 g (87%). The yield after StepB was 0.27 g (54%). The yield of the target compound obtained from StepC was 137 mg (68.5%).

Example 313

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.91 g (91%). The yield after StepB was 0.34 g (68%). The yield of the target compound obtained from StepC was 36.5 mg (18%).

Example 314

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.76 g (76%). The yield after StepB was 0.28 g (56%). The yield of the target compound obtained from StepC was 99.8 mg (50%).

Example 315

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.86 g (86%). The yield after StepB was 0.31 g (62%). The yield of the target compound obtained from StepC was 93.6 mg (47%).

Example 316

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.93 g (93%). The yield after StepB was 0.23 g (46%). The yield of the target compound obtained from StepC was 96.8 mg (49%).

Example 317

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.84 g (84%). The yield after StepB was 0.33 g (66%). The yield of the target compound obtained from StepC was 55.1 mg (28%).

Example 318

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.79 g (79%). The yield after StepB was 0.34 g (68%). The yield of the target compound obtained from StepC was 20.5 mg (10%).

Example 319

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.84 g (84%). The yield after StepB was 0.29 g (58%). The yield of the target compound obtained from StepC was 57.5 mg (29%).

Example 320

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.92 g (92%). The yield after StepB was 0.31 g (62%). The yield of the target compound obtained from StepC was 112.6 mg (56%).

Example 321

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.88 g (88%). The yield after StepB was 0.29 g (58%). The yield of the target compound obtained from StepC was 142.7 mg (71%).

Example 322

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.94 g (94%). The yield after StepB was 0.30 g (60%). The yield of the target compound obtained from StepC was 112.2 mg (56%).

Example 323

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.69 g (69%). The yield after StepB was 0.26 g (52%). The yield of the target compound obtained from StepC was 15.2 mg (8%).

Example 324

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.90 g (90.5%). The yield afterStep B was 0.35 g (70%). The yield of the target compound obtained fromStep C was 71.1 mg (35.5%).

Example 325

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.93 g (93%). The yield after StepB was 0.27 g (54%). The yield of the target compound obtained from StepC was 77.2 mg (38%).

Example 326

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.89 g (89%). The yield after StepB was 0.32 g (64%). The yield of the target compound obtained from StepC was 19.8 mg (10%).

Example 327

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.79 g (79%). The yield after StepB was 0.29 g (58%). The yield of the target compound obtained from StepC was 174.8 mg (87%).

Example 328

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.91 g (91%). The yield after StepB was 0.34 g (68%). The yield of the target compound obtained from StepC was 42.8 mg (21%).

Example 329

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.88 g (88%). The yield after StepB was 0.27 g (54%). The yield of the target compound obtained from StepC was 82.7 mg (41%).

Example 330

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.94 g (94%). The yield after StepB was 0.24 g (48%). The yield of the target compound obtained from StepC was 180.5 mg (90%).

Example 331

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.87 g (87%). The yield after StepB was 0.30 g (60%). The yield of the target compound obtained from StepC was 116.8 mg (58%).

Example 332

The target compound was prepared according to the procedure described inScheme 17 for compound 76 using the appropriate reagents and startingmaterials. The yield after Step A was 0.85 g (85%). The yield after StepB was 0.27 g (54%). The yield of the target compound obtained from StepC was 31.5 mg (16%).

Example 333

Compound 79a was prepared according to the procedure described in StepA-B, Scheme 18 in 15% yield. The mixture of 79a (0.25 mmol) and 6Naqueous HCl (5 ml) was stirred at 50° C. for 5 h. The resulting solutionwas evaporated to dryness. The residue was triturated with dioxane anddried in vacuo to give pure target compound as the HCl salt in 90%yield.

Example 334

Compound 79b was prepared according to the procedure described in StepA-B, Scheme 18 in 17% yield. The mixture of 79b (0.25 mmol) and 6Naqueous HCl (5 ml) was stirred at 50° C. for 5 h. The resulting solutionwas evaporated to dryness. The residue was triturated with dioxane anddried in vacuo to give pure target compound as the HCl salt in 90%yield.

Example 335

Compound 79c was prepared according to the procedure described in StepA-B, Scheme 18 in 19% yield. The mixture of 79c (0.25 mmol) and 6Naqueous HCl (5 ml) was stirred at 50° C. for 5 h. The resulting solutionwas evaporated to dryness. The residue was triturated with dioxane anddried in vacuo to give pure target compound as the HCl salt in 90%yield.

Example 336

Compound 79d was prepared according to the procedure described in StepA-B, Scheme 18 in 13% yield. The mixture of 79d (0.25 mmol) and 6Naqueous HCl (5 ml) was stirred at 50° C. for 5 h. The resulting solutionwas evaporated to dryness. The residue was triturated with dioxane anddried in vacuo to give pure target compound as the HCl salt in 90%yield.

Example 337

The target compound was prepared as described in Scheme 19, using theappropriate organozinc reagent (13% yield).

Example 338

The target compound was prepared as described in Scheme 19, using theappropriate organozinc reagent (19% yield).

Example 339

The target compound was prepared as described in Scheme 19, using theappropriate organozinc reagent (17% yield).

Example 340

The target compound was prepared as described in Scheme 19, using theappropriate organozinc reagent (12% yield).

Example 341

The target compound was prepared as described in Scheme 19, using theappropriate organozinc reagent (11% yield).

Example 342

The target compound was prepared as described in Scheme 19, using theappropriate organozinc reagent (15% yield).

Example 343

Step A: Sodium (2.27 g, 4 eq) was dissolved in MeOH (80 ml). To thissolution, compound 85 (4 g, 1 eq) and amidine hydrochloride (3.88 g, 1eq) was added. The resulting mixture was heated at 65° C. for 12 hoursand evaporated in vacuo. The residue was taken up with cold water (10ml), acidified with HCl conc. to pH=4 and allowed to stand in fridge for2 hours. The precipitate was filtered, washed with water 10 ml and driedto obtain compound 86 (4.3 g).

Step B: To a suspension of compound 86 (4.3 g) in POCl₃ (35 ml), DMF(0.5 ml) was added. The reaction mixture was heated at 90° C. for 12 hand evaporated. The residue was quenched with ice-cold water (50 ml) andextracted with MTBE (3*50 ml). The organic extracts was washed withbrine (2*50 ml), dried over Na₂SO₄ and evaporated in vacuo to obtaincompound 87 (2.3 g).

Step C: To a solution of compound 87 (0.5 g, 1 eq) in DMF 5 ml was addedphenol (0.32 g, 1 eq.) and K₂CO₃ (0.4 g,1.5 eq). The resulting mixturewas heated at 70° C. for 12 h, cooled, taken up with water (50 ml) andextracted with MTBE (3*30 ml). The organic extracts was washed withbrine (2*30 ml), dried over Na₂SO₄ and evaporated in vacuo to obtaincompound 88 (˜0.6 g, 70% purity). This compound was used for the nextstep without purification.

Step D: To a solution of compound 88 (0.2 g, 1 eq) in THF (10 ml), asolution of NaOH (0.1 g, 5 eq) in water (2 ml) was added. The resultingmixture was stirred at 60° C. for 12 h, acidified with HCl andevaporated. The residue was purified by HPLC to give the targetcompound.

Example 344

To a solution of compound 88, prepared as described in Step C, Example343 (0.2 g, 1 eq) in dry MeOH (20 ml), t-BuOK (0.06 g, 1 eq) was added.The resulting mixture was stirred at 25° C. for 12 h and evaporated. Theresidue was purified by HPLC to give the target compound.

Example 345

To a solution of compound 89 (Example 344), prepared as described inExample 338 (0.6 g, 1 eq) in DCM (40 ml), BBr3 (1.2 g, 3 eq) was added.The resulting mixture was stirred at 25° C. for 12 h and evaporated invacuo. The residue was quenched with water (10 ml) and extracted withDCM (3*30 ml). The organic extract was dried over Na₂SO₄ and evaporatedunder reduced pressure. The residue was purified by HPLC to give thetarget compound.

This disclosure is not to be limited in scope by the embodimentsdisclosed in the examples which are intended as single illustrations ofindividual aspects, and any methods which are functionally equivalentare within the scope of this disclosure. Indeed, various modificationsin addition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

Various references such as patents, patent applications, andpublications are cited herein, the disclosures of which are herebyincorporated by reference herein in their entireties.

What is claimed is:
 1. A compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein: R¹ isheteroaryl; R² is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo,OR³, alkoxycarbonyl, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷; R⁸ isselected from the group consisting of alkyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, heteroaryloxy, and C(O)R⁴; R³ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; R⁴ is hydrogen,hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, cycloalkyl, aralkyl, alkenyloxy, alkynyloxy, aryloxy,alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or —NR⁶R⁷; R⁵ ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl; R⁶ andR⁷ are independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,aryl sulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl and alkylsulfonyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached; and p is 0-2; with theproviso that when R² is alkoxy, then R⁴ is not methyl, and with thefurther proviso that the compound is not:


2. The compound of claim 1, wherein the compound of Formula VII

is a compound of Formula VIIa: or a pharmaceutically acceptable saltthereof, wherein: R^(1a) is heteroaryl; R^(2a) is alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo,OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷; R^(2a) is alkyl; R^(8a)is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; R⁴ ishydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy,aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or—NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, aryl sulfonyl, heteroarylsulfonyl,cycloalkylsulfonyl and alkylsulfonyl, or R⁶ and R⁷ are combined to forma cyclic structure including the nitrogen atom to which they are bothattached; and p is 0-2; with the proviso that when R^(2a) is alkoxy,then R^(8a) is not methyl.
 3. A compound of Formula VIIt:

or a pharmaceutically acceptable salt thereof, wherein: R¹, R² and R⁸are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷; R³ ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; R⁴ ishydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy,aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or—NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, aryl sulfonyl, heteroarylsulfonyl,cycloalkylsulfonyl and alkylsulfonyl, or R⁶ and IC are combined to forma cyclic structure including the nitrogen atom to which they are bothattached; R* is heteroaryl; and p is 0-2.
 4. The compound of claim 3,wherein: R¹ is heteroaryl; and R⁸ is selected from the group consistingof alkyl, aryl, heteroaryl, OR³, C(O)R⁴, and NR⁶R⁷.
 5. The compound ofclaim 1, wherein: R² is selected from the group consisting of alkyl,OR³, and NR⁶R⁷; R⁸ is selected from the group consisting of alkyl, aryl,heteroaryl, heteroaryloxy, and C(O)R⁴; R³ is hydrogen or alkyl; R⁴ is—NR⁶R⁷; and R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, aryl, and heteroaryl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached.
 6. The compound of claim 1, wherein the compoundis:


7. A pharmaceutical composition comprising the compound of claim 1 and apharmaceutical acceptable carrier, diluent or excipient.
 8. Apharmaceutical composition comprising the compound of claim 2 and apharmaceutical acceptable carrier, diluent or excipient.
 9. Apharmaceutical composition comprising the compound of claim 3 and apharmaceutical acceptable carrier, diluent or excipient.
 10. Apharmaceutical composition comprising the compound of claim 4 and apharmaceutical acceptable carrier, diluent or excipient.
 11. Apharmaceutical composition comprising the compound of claim 5 and apharmaceutical acceptable carrier, diluent or excipient.
 12. Apharmaceutical composition comprising the compound of claim 6 and apharmaceutical acceptable carrier, diluent or excipient.
 13. A method ofinhibiting the function of one or more members of the Ras superfamily,comprising administering to a subject a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein: R¹ isheteroaryl; R² is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo,OR³, alkoxycarbonyl, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷; R⁸ isselected from the group consisting of alkyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, heteroaryloxy, and C(O)R⁴; R³ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; R⁴ is hydrogen,hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, cycloalkyl, aralkyl, alkenyloxy, alkynyloxy, aryloxy,alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or —NR⁶R⁷; R⁵ ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl; R⁶ andR⁷ are independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,aryl sulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl and alkylsulfonyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached; and p is 0-2; with theproviso that when R² is alkoxy, then R⁸ is not methyl, and with thefurther proviso that the compound is not:

and wherein the administered compound of Formula VII inhibits thefunction of one or more members of the Ras superfamily.
 14. The methodof claim 13, wherein the compound is a compound of Formula VIIa:

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) isheteroaryl; R^(2a) is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷; R^(8a) is H or alkyl; R³ is hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; R⁴ is hydrogen,hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy,aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or—NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, aryl sulfonyl, heteroarylsulfonyl,cycloalkylsulfonyl and alkylsulfonyl, or R⁶ and IC are combined to forma cyclic structure including the nitrogen atom to which they are bothattached; and p is 0-2; with the proviso that when R^(2a) is alkoxy,then R^(8a) is not methyl.
 15. A method of inhibiting the function ofone or more members of the Ras superfamily, comprising administering toa subject a compound of Formula VIIt:

or a pharmaceutically acceptable salt thereof, wherein: R¹, R² and R⁸are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷; R³ ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; R⁴ ishydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy,aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or—NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, aryl sulfonyl, heteroarylsulfonyl,cycloalkylsulfonyl and alkylsulfonyl, or R⁶ and R⁷ are combined to forma cyclic structure including the nitrogen atom to which they are bothattached; R* is alkyl, aryl or heteroaryl; and p is 0-2; wherein theadministered compound of Formula VIIt inhibits the function of one ormore members of the Ras superfamily.
 16. The method of claim 15,wherein: R¹, R² and R⁸ are independently selected from the groupconsisting of heteroaryl and OR³; R³ is hydrogen or alkyl; and R* isaryl or heteroaryl.
 17. The method of claim 13, wherein: R¹, R² and R⁸are independently selected from the group consisting of heteroaryl,C(O)R⁴, and NR⁶R⁷; R³ is hydrogen or alkyl; R⁴ is —NR⁶R⁷; and R⁶ and R⁷are independently selected from the group consisting of hydrogen, alkyl,aryl, and heteroaryl, or R⁶ and R⁷ are combined to form a cyclicstructure including the nitrogen atom to which they are both attached.18. The method of claim 13, wherein the compound of Formula VII isselected from the group consisting of:


19. The method of claim 13, wherein the compound of Formula VIIa isselected from the group consisting of:


20. The method of claim 15, wherein the compound is selected from thegroup consisting of:


21. The method of claim 13, wherein the compound is selected from thegroup consisting of:


22. The method of claim 13, wherein the subject has cancer.
 23. Themethod of claim 22, wherein the one or more members of the Rassuperfamily is Ras protein.
 24. The method of claim 23, wherein thecompound inhibits GTP binding to the Ras protein GTP binding domain withgreater than 25% inhibition at 20 uM in a cell-free-assay.
 25. Themethod of claim 24, wherein the Ras protein is HRAS, KRAS, or NRAS, or amutant thereof.
 26. The method of claim 22, wherein the cancer is ablood cancer, hepatocellular carcinoma, prostate cancer, pancreaticcancer, lung cancer, ovarian cancer, colon cancer, small intestinecancer, biliary tract cancer, endometrium cancer, skin cancer(melanoma), cervix cancer, urinary tract cancer, or glioblastoma. 27.The method of claim 15, wherein the subject has cancer.
 28. The methodof claim 27, wherein the one or more members of the Ras superfamily isRas protein.
 29. The method of claim 28, wherein the compound inhibitsGTP binding to the Ras protein GTP binding domain with greater than 25%inhibition at 20 uM in a cell-free-assay.
 30. The method of claim 29,wherein the Ras protein is HRAS, KRAS, or NRAS, or a mutant thereof.